ENDOTHELIN CONVERTING ENZYME INHIBITORS

Abstract: A class of compounds which are effective inhibitors of the endothelin converting enzyme (ECE) and therefore useful in the treatment of cardiovascular diseases such as stroke. The invention also includes pharmaceutical compositions containing such compounds.

Description: ENDOTHELIN CONVERTING ENZYME INHIBITORS The present invention relates to compounds which show inhibition of endothelin converting enzyme (ECE), to pharmaceutical compositions containing such compounds and to their use in animal and human medicine. Endothelins (ETs) are highly homologous 21 amino acid polypeptides and are formed in human and other mammalian cells and tissues from the corresponding big endothelin 21 22 1 22 (BETs) precursors through hydrolysis of a Trp -Val or a Tip - He bond by ECE to form the ETs. ETs have potent and sustained smooth muscle contractile actions, in particular ET-1 and ET-2 are the most potent and long-acting of known vasoconstrictor substances. ETs are known to be associated with a wide variety of pathological states (Doherty A.M. J.Med.Chem 35/9 pl493-1508[1992]) and it has been postulated that there may exist the potential for therapy of such disease states by interference with ET receptors (Doherty A.M. ibid) or by inhibition of ECEs (JP 4-41430, WO 92/13545 and WO 92/12170). A class of compounds has now been found which are effective ECE inhibitors. Such compounds are useful in treatment of myocardial infarction, angina pectoris, cerebral infarction (stroke), cerebral vasospasm, ischemic cardiac insufficiency, Raynaud's disease and other vasospastic diseases, atherosclerosis, essential hypertension, pulmonary hypertension, asthma, respiratory distress syndrome, acute renal failure, cyclosporin-induced renal failure, endotoxic shock, endotoxin-induced multiple organ failure, acute failure following organ transplantation, Crohn's disease, ulcerative colitis, gastric ulcer, escleroderma and lupus erythematosus. The present invention provides peptide compounds of formula (I) or a salt thereof, wherein: R\ is C5.7 aryl; C5.7 aryl Cj_7 alkyl; C5.7 aryl Cj_4 alkoxy; C5_7 aryloxy- Cι_4 alkyl; carboxy Cj_4 alkyl; C]_4 alkoxycarbonyl C]_4 alkyl; Cj_4 alkyl or di- phenyl C]_4 alkyl, such aryl groups or aryl moieties of aryl-containing groups being optionally substituted with Cj_4 alkyl, halo, nitro, carboxyl or sulphonyl, or R] is a group of formula Ila, lib or lie: where n = O or 1 ; where n = O or 1 and where Z is -CONH- or -CH2- and R5 is benzyloxy; 1,2,3,6 tetrahydro-2,6-dioxo-4-pyrimidinyl; or 2,5 dioxo-4-imidazolidinyl; or where R is hydrogen or Cι_4 alkyl; R2 is indol-3-yl-methyl; C5.7 aryl; or C5.7 aryl Cj_4 alkyl, such aryl groups or aryl- moieties of aryl-containing groups being optionally substituted with hydroxy or halo; benzothienylmethyl; or Cj_4 alkyl; R3 is formyl; maleimidomethyl; methoxycarbonylvinyl; dimethoxymethyl; semicarbazonomethyl; Cj_4 alkyl; R4 dithio; R4 dithio-Cj^ alkyl; R4 dithioacetyl; R7 Cι_4 aikylamido; R7 C]_4 alkylamidomethyl; -CORg; - CH(OH)R9; -COCOR 10 ;or - COC ≡ CR j 1, in which R4 is C1- alkyl, C5.7 aryl or Cj_4 alkyl C5.7 aryl; R7 is acetoxy, halo, maleimido or hydroxy; Rg is CH2 CH; CHO; C,ι_4 alkenyl, Cι_4 alkylhalo or C ] _4 alkylthio; R9 is CHO, Cj_4 alkenyl or CH2-CH-, such oxiranyl moiety being optionally substituted with Cι_4 alkyl or Cj_4 alkoxycarbonyl; RJQ is C\. 4 alkoxy; C5.7 aryloxy; Cj_4 alkyl, hydrogen; hydroxy or methoxycarbonyl; and R\ j is hydrogen or Si(CH3); such aryl groups or aryl moieties of aryl-containing groups being optionally substituted with nitro or carboxy; X is benzyl optionally substituted with C1.4 alkoxy or halo; Cι_4 alkyl; indol-3-yl- methyl; naphthylmethyl; benzyloxybenzyl or cyclo C\. alkylmethyl; and Y is benzyl optionally substituted with Cι_4 alkyl or Cj_4 alkoxy; indol-3-yl-methyl; naphthylmethyl; benzyloxybenzyl or Cι_4 alkyl. Preferably R is C5.7 aryl Cj_4 alkoxy; C5.7 aryl Cι_4 alkyl; C5.7 aryloxy Cj_4 alkyl 1 s or is a group of Formula Ila or lib where n=O or 1 and where Z is -CONH-or-CH2 and R5 is benzyloxy; 1,2,3,6 tetrahydro-2,6-dioxo-4-pyrimidinyl or 2,5,dioxo-4- imidazolidinyl, or is a group of Formula He where R is hydrogen or C 1.4 alkyl. Preferably R2 is indol-3yl-methyl; phenyl or benzyl optionally substituted with halo or hydroxy. Preferably R3 is formyl; semicarbazonomethyl; -CORg; R7 Cj_4 aikylamido or R7 C1.4 alkylamidomethyl; in which Rg is CH2 CH-; CHO; Cι_4 alkenyl, Cj_4 alkylhalo or C 1.4 alkylthio and R7 is acetoxy, halo, maleimido, or hydroxy. Preferably X is benzyl optionally substituted with halo; indol- 3-yl-methyl; naphthyl¬ methyl; Cj_4 alkyl; or benzyloxybenzyl. Preferably Y is naphthylmethyl; indol-3-yl-methyl, benzyloxybenzyl; Cj_4 alkyl; benzyloxyCι_4 alkyl. More preferably Ri is benzyloxy; [5-(hexahydro-2-oxo-lH-thieno (3,4-d]imidazol-4-yl) valeramido]pentyl; 6-[6-[(l,2,3,6-tetrahydro-2,6-dioxo-4-pyri_midinyl) formamido] hexanamido] pentyl; 6-[6-(benzyloxy) formamido] hexanamido] pentyl; 12- [(benzyloxy) acetamido] undecanyl; 5-phenylbutyl; phenoxyethyl; 5-(hexahydro-2-oxo- (lH-thieno(3,4-d) imidazol-4-yl)butyl; 3-pyridylmethoxy; benzyl; 2-phenylethyl, 3- phenylethyl; N-[(benzyloxy) carbonyl)]-4-O-tert-butyl-L-aspart-l-yl; N-[(benzyloxy) carbonyl)]-L-aspart-l-yl; 6-[6-[2-(2,5-dioxo-4-imidazolidinyl) acetamido] hexanamido] pentyl; 3-pyridylmethoxy; 6-benzyloxycarbonylaminopentyl. More preferably, R2 is indol-3-yl methyl, chlorobenzyl; bromobenzyl; phenyl; benzyl, 4-hydroxy benzyl. More preferably, R3 is formyl; 2-oxiranylcarbonyl; semicarbazonomethyl; glyoxyloyl; acryloyl; chloroacetyl; 2-chloroacetyl; 2-acetoxyacetamido; (2-chloro-acetamido) methyl; (2-maleimidoacetamido)-methyl; 3-(malemidoacetamido)-methyl; 1- maleimidomethyl; propynoyl; (3-maleimidopropionamido) methyl. More preferably, X is indol-3-yl-methyl; bromobenzyl; 1-napthylmethyl; iodobenzyl; benzyloxybenzyl; [S]-l-methylpropyl; 2-napthylmethyl; benzyl; methyl; 4- chlorobenzyl; 2-methylpropyl; 1-methylethyl. More preferably, Y is indol-3-yl-methyJ; T-naphthylmethyl; 2-napthylmethyl; benzyloxybenzyl; 4-ethoxybenzyl; [S]-methylpropyl and, 1-methylethyl. Particularly preferred compounds of the present invention are those wherein Rj is 5- (hexahydro-2-oxo-lH thieno [3,4-d] imidazol-4-yl) butyl or benzyloxy; R2 is indol-3- yl-methyl or phenyl and R3 is formyl or oxiranylcarbonyl; X is bromobenzyl, iodobenzyl or indol-3-yl-methyl, and Y is 2-napthylmethyl or indol-3-yl-methyl. Most preferred embodiments of the present invention include compounds selected from the group comprising: N-[5-(hexahydro-2-oxo- 1 H-thieno[3 ,4-d]imidazol-4-yl)pentanoyl]- 1 -p- bromophenylalanyl-L-l-naphthylalanyl-L-N-[l-foπnyl]2-(lH-indol-3-yl)ethyl].amide; or N-[5-(liexahydro-2-oxo-lH-thieno[3,4-d]imidazol-4-yl)pentanoyl]-L-tryptophanyl-L- tryptophan-L-N-[ 1 -formyl]2-( 1 H-indol-3-yl)ethyl]amide; or N-(benzyloxy)carbonyl-L-p-bromophenylalanyl-L- 1 -naphthylalanyl-L-N-[ 1 - {2- oxiranylcarbonyl]]2-phenylethyl]amide; or N-Benzyloxycarbonyl-S-p-bromophenylalanyl-S- 1 'naphthylalanyl- 1 -S-formyl- 1 -( 1 H- indol-3-yl-methyl)-methylamide; or N-Benzyloxycarbonyl-S-p-bromophenylalanyl-S-2'naphthylalanyl- 1 -S-formyl- 1 -(1 H- indol-3-yl-methyl)-methylamide; or N-Benzyloxycarbonyl-S-tryptophanyl-S- 1 'naphthylalanyl- 1 -S-formyl- 1 -( 1 H-indol-3-yl- methyl)-methylamide; or a salt thereof. N-Benzyloxycarbonyl-S-p-iodophenylalanyl-S- 1 'naphthylalanyl- 1 -S-formyl- 1 -( 1 H- indol-3-yl-methyl)-methylamide; or a salt thereof. N-[5-(hexahydro-2-oxo-lH-thieno[3,4-d]imidazol-4-yl)pentanoyl]-L-p- bromophenylalanyl-L- 1 -naphthylalanyl-L-N-[ 1 -foπnyl]2-( 1 H-indol-3-yl)ethyl]amide; or N-[5-(hexahydro-2-oxo-lH-thieno[3,4-d]imidazol-4-yl)pentanoyl]-L-tryptophanyl-L- tryptophan-L-N-[l-formyl]2-(lH-indol-3-yl)ethyl]amide;or N-(benzyloxy)carbonyl-L-p-bromophenylalanyl-L-l-naphthylalanyl-L-N-[l-[2- oxiranylcarbonyl]]2-phenylethyl]amide; or N-Benzyloxycarbonyl-S-p-bromophenylalanyl-S- 1 'naphthylalanyl- 1 -S-formyl- 1 -( 1 H- indol-3-yl-methyl)-methylamide; N-Benzyloxycarbonyl-S-p-bromophenylalanyl-S- 1 'naphthylalanyl- 1 -S-formyl- 1 -( 1 H- indol-3-yl-methyl)-methylamide; or a salt thereof. The present invention further comprises a compound of Formula (III) or a salt thereof; wherein R\ is selected from the group comprising C5.7 aryl; C5.7 aryl Cι_4 alkyl; carboxy Cj__4 alkyl; C1. alkyl and C5.7 aryl Cj_4 alkoxy; such aryl groups or aryl moieties of aryl- containing groups being optionally substituted with Cj_4 alkyl, halo, nitro, carboxyl or sulphonyl; wherein R2 1 is methyl R2 and R2' is selected from the group comprising indol-3-yl; phenyl; isobutyl and benzothienyl; and R3 is selected from the group comprising formyl; glyoxyloyl; haloacetyl; Cj_4 alkoxalyl; C5.7 aryloxalyl;R4 dithio;R4 dithio Cι_4 alkyl;R4 dithioacetyl; ι_4 alkyl;acryloyl and 2-oxiranylcarbonyl such oxiranyl being optionally substituted with a Cι_4 alkyl or C^ alkoxycarbonyl and R4 is selected from the group comprising Cι_4 alkyl, C5.7 aryl and Cι_4 alkyl C5.7 aryl; such aryl groups or aryl moieties of aryl-containing groups being optionally substituted with nitro or carboxyl. Compounds of the present invention may exist as different optical isomers the nature of which will depend upon whether each modified amino acid residue is present in its & or E chiral form. The present invention includes within its scope each possible optical isomer substantially free is associated with less than 5%, of any other optical isomer(s), and mixtures of one or more optical isomers in any proportions, including racemic mixtures. Preferred compounds of the present invention include those wherein all chiral centres are present in their £ chiral form. Compounds of formula (I) wherein R is formyl may be prepared by reduction of their respective N,O-dimethylhydroxamide precursors with lithiumaluminium hydride (Fehrent^ J.A., Castro, B., Synthesis 1983 p676-678). The N,O-dimethylhydroxamide precursors may be obtained by coupling of a protected dipeptide (sg N- Benzyloxycarbonyl(CBZ)-isoleucyl-isoleucyl-OH: Bachem Bioscience Inc.) with the appropriate amino acid N,O-dimethylhydroxamide (Nahm S., Weinreb S., Tet. Lett. 22 3815-3818, [1981]). or its hydrochloride salt. The amino acid N,O- dimethylhydroxamides may be prepared from carbobenzyloxy protected amino acids (Bachem Biosciences) and N,O-dimethylhydroxylamine (Fluka) under standard peptide coupling conditions (Houben-Weyl, Methoden Der Organischen Chemie, 4, Aufl.. Vol. 15/1 E.Muller Ed, [1974]) followed by hydrogenolytic deprotection (Houben-Weyl ibid). The aminoacid N,O-dimethylhydroxamide hydrochloride salts may be prepared from t- butyloxy-carbonyl (BOC) protected amino acids (Bachem Bioscience) and N,O- dimethylhydroxylamine (Fluka) in the manner described above, followed by acidolytic deprotection with 4N HCl/dioxane (Pierce) (Burton, J., Topper, R., Ehrlich, R. in Peptides: Structure and Biological Functions, Gross, E. .and Meienhofer, J., Eds., Pierce, Rockford, IL, 605-608,[1979]. Alternatively, the N,O-dimethylhydroxamide precursors may be obtained by coupling a CBZ-protected amino acid to the hydrochloride salt of a dipeptide N,O- dimethylhydroxamide under standard peptide coupling conditions (Houben-Weyl, ibid.). The hydrochloride salt of the dipeptide N,O-dimethyl- hydroxamide may be obtained from acidolysis of the corresponding Boc-protected dipeptide N,O- dimethylhydroxamide using 4N HCl/dioxane in the manner previously described. The Boc-protected dipeptide N,O-dimethyl-hydroxamide may in turn be prepared by coupling a Boc-protected amino acid with the hydrochloride salt of an amino acid N,O- dimethylhydroxamide under standard peptide coupling procedures (Houben-Weyl, ibid.). In another method, the N,O-dimethylhydroxamide precursors may be obtained by treatment of the hydrochloride salt of a tripeptide N,O-dimethyl-hydroxamide with benzyl chloroformate (Bergmann, M., Zervas, L., Ber. dtsch. Chem. Ges. (1932), 65, 1192). The hydrochloride salt may be obtained by acidolysis of the corresponding Boc- protected tripeptide N,O-dimethyl-hydroxamide using 4N HCl/dioxane as previously described. The Boc-protected tripeptide may be obtained by coupling a Boc-protected amino acid to the hydrochloride salt of a dipeptide N,O-dimethylhydroxamide under standard peptide coupling conditions (Houben-Weyl, ibid.). Additionally, the N,O-dimethylhydroxamide precursors may be synthesized by reacting a CBZ-protected amino acid with the free amine of a dipeptide N,O- dimethylhydroxa ide under standard peptide coupling conditions (Houben-Weyl, ibid.). The dipeptide N,O-dimethylhydroxamide may be prepared by hydrogenolysis of a CBZ-protected dipeptide N,O-dimethylhydroxamide. The CBZ-protected dipeptide N,O-dimethylhydroxyamide may in tum be synthesized by reacting a CBZ-protected dipeptide with N,O-dimethylhydroxylamine. Compounds of formula (I) wherein R is acryloyl may be prepared from N,O- dimethylhydroxamide precursors by treatment with excess vinyl magnesium bromide (Lancaster Chemicals), (Nahm and Weinreb ibid). The synthesis of such N,O- dimethylhydroxamide precursors is discussed above. Compounds of formula (I) wherein R3 is 3-(trimethylsilyl)-2-propynoyl are prepared from the N,O-dimethylhydroxamide precursors by treatment with excess lithiated trimethylsilylacetylene (Aldrich Chemicals) (Nahm and Weinreb, ibid). The synthesis of the N,O-dimethylhydroxamide precursors is discussed above. Compoimds of formula (I) wherein R3 is 2-alkynyl are prepared from compounds of formula (I) where R3 is 3-(trimethylsilyl)-2-propynoyl described above, by treatment with methanolic sodiumbicarbonate. Compounds of formula (I) wherein R3 is (E)-2-(methoxycarbonyl)vinyl are prepared from compounds of formula (I) by treatment with methoxycarbonylmethyltriphenylphosphorane (Aldrich Chemicals). Compoimds of formula (I) wherein R is glyoxyloyl may be obtained from compounds of formula (I) wherein R is acryloyl (described above) by ozonolysis, followed by reduction with dimethyl sulfide (Angelastro et al., J.Med.Chem. 21 13-16, 1990). Compounds of formula (I) wherein R3 is 2-oxiranylcarbonyl are prepared from compounds of formula (I) wherein R3 is acryloyl (described above) by reduction to the allylic alcohol derivative (Luche, J.L., J.Am.Chem.Soc, 1978, 2227-2228), followed by oxidation with m-chloroperbenzoic acid (Cella, J.A., McGrath, J.P., Kelly, J.A., El Soukkary, O., Hilpert, L., J.Org.Chem, 1977, 42, 2077-2080) to the oxiranyl alcohol and further oxidation with dimethylsulfoxide/acetic anhydride (Mancuse, A.J., Swen, D., Synthesis, 1981, 165-185). Compounds of formula (I) wherein R3 is 1-hydroxyallyl are prepared by reduction of compounds of formula (I) where R3 is acryloyl according to Luche, J.L .Am. Chem. Soc, 1978, 2227-2228. Compounds of formula (I) wherein R3 is hydroxy(2-oxiranyl)methyl are prepared from compounds of formula (I) where R3 is 1-hydroxyallyl by oxidation with m- chloroperbenzoic acid (Cella, J.A., McGrath, J.P., Kelly, J.A., El Soukkary, O., Hilpert, L., J.Org.Chem 1977, 42, 2077-2080). Compounds of formula (I) wherein R3 is formylhydroxymethyl are prepared from compounds of formula (I) where R3 is 1 -hydroxyallyl, by ozonolysis, followed by reduction with dimethylsulfide (Angelastro et al, J.Med.Chem. 1990, 33, 13-16). Compounds of formula (I) wherein R is haloacetyl may be obtained by coupling of N- protected dipeptide (eg CBZ-isoleucyl-isoleucyl-OH from Bachem Bioscience, Inc.) with the appropriate amino acid halomemylketone using a standard peptide coupling reaction. The halomethylketones may be prepared from commercially purchased amino acids (Bachem Biosciences, Inc.) using published procedures (Garcia-Lopez, M.T., Gonzalez-Muniz, R., Harto, J.R. Tetrahedron, 1988, p 5131-5138) followed by deprotection with trifluoroacetic acid (Houben-Weyl ibid). Compounds of formula (I) wherein R is alkoxalyl may be obtained by ozonolysis of the 2-alkoxyvinyl ketone precursor followed by reduction with dimethylsulphide (Angelastro M.R., et al J.Med.Chem. 21 13-16, 1990). The precursor may be prepared from the appropriate N,O-dimethylhydroxamide precursor by addition of lithiated alkylvinylether (Angelastro et al ibid). Compounds of formula (I) wherein R3 is dimethoxymethyl are prepared from compounds of formula (I) where R3 is formyl by treatment with trimethylorthoformate and pyridinium p-toluenesulfonate in methanol (Meskens et al, Synthesis 1981, 1501- 1521). Compounds of formula (I) wherein R3 is pyruvoyl are prepared by hydrolysis of the 2- alkoxyvinyl ketone precursor (Angelastro M.R. et al J.MedChem. 1990, 33, 13-16). The precursor may be obtained from the appropriate N,O- dimethylhydroxamide precursor by addition of lithiated alkylvinylether (Angelastro et al, ibid). Compounds of formula (I) wherein R3 is semicarbazonomethyl are prepared from compounds of formula (I) where R3 is formyl by treatment with semicarbazide and sodium acetate. Compounds of formula (I) wherein R3 is 2-(acetylthio)acetyl are prepared from compounds of formula (I) where R3 is 2-chloroacetyl (see above) by treatment with thioacetic acid (Aldrich Chemicals) (Spaltenstein et al, J.Org.Chem., 1987 52, 3759- 3766). Compounds of formula (I) wherein R3 is R4-dithiomethyl may be prepared by treatment of the methylenethiol precursor with the appropriate mixed disulfide containing R4-thiol and 5-nitropyridine-2-thiol. The mixed disulfides may be obtained by disulfide exchange reaction between commercially available 2,2'-dithiobis(5-nitropyridine) (Janssen Chemicals) and the desired thiol (Aldrich Chemicals) (Trans, J.P., Shen Z-Y, Int. J.Peptide Pro.Res., 1992, 39, 464-471 and Foumic-Zaluski, M-C, J.Med.Chem., 1992, 35, 2472-2481). Methylenethiol precursors may be prepared from commercially available (Bachem Biosciences) Boc-amino alcohols by treatment with methanesulfonyl chloride, followed by potassium thioacetate (Spaltenstein et al, ibid) and deprotection with trifluoroacetic acid and ammonium hydroxide (Houben-Weyl, ibid), followed by coupling to commercially available CBZ-protected dipeptides (Bachem Bioscience) (Houben-Weyl, ibid). Compounds of formula (I) wherein R is R dithioalkyl or R dithioacetyl alkyl may be prepared by treatment of the methylenethiol or thiomethylketone respectively precursor with the appropriate mixed disulphide containing 5 nitropyridine-2-thiol. The mixed disulphides may be obtained by a disulphide exchange reaction between commercially available 2,2'dithiobis(5-nitropyridine) (Janssen Chem) and the desired thiol (Trans, J.P., Shen Z-Y, Int. J. Peptide Protein Res., 199221464-471 and Foumic-Zaluski M-C. et al. J. of Med. Chem. 1992 21 2473-2481). The thiols are either commercially available, or are themselves the thiomethylketones or methylenethiols described immediately hereafter. These thiomethylketone precursors may be obtained from chloromethylketones such as compounds of formula (I) wherein R3 is haloacetyl (synthesis ibid) by treating with thioacetic acid (Aldrich Chemicals) (Spaltenstein, A. et al J.Org.Chem. 1987, 12 3759- 3766) followed by deprotection with ammonium hydroxide (Houben-Weyl ibid). Methylenethiols may be prepared from commercially available (Bachem Bioscience, Inc.) Boc-aminoalcohols by treatment with methanesulphonyl chloride, followed by potassium thioacetate (Spaltenstein et al ibid) and deprotection with trifluoroacetic acid and ammonium hydroxide (Houben-Weyl ibid). Compounds of formula (I) wherein R3 is glycolylamidomethyl, 2- chloroacetamidomethyl, 2-maleimidoacetamidomethyl, 3-maleimidoacetamidomethyl and [[[3-(ethoxycarbonyl)2-oxiranyl]carbonyl]amino]methyl are prepared by acylation of the methyleneamino precursor with appropriate commercially available (Aldrich and TCI Chemicals) acid precursor (Houben-Weyl, ibid). The methyleneamino precursors may be obtained by reduction of the corresponding azido compounds with triphenylphosphine in aqueous tetrahydrofuran. The azido compounds in turn are prepared from commercially available Boc-aminoalcohols (Bachem Biosciences) by mesylation, followed by displacement with lithium azide (Spaltenstein et al, ibid), deprotection with trifluoroacetic acid and coupling with the appropriate commercially available dipeptide (Bachem Biosciences) (Houben-Weyl, ibid). Compounds of formula (I) wherein R3 is 2-acetoxyacetamido are prepared from the corresponding free amino compounds by acylation with commercially available acetoxyacetylchloride (Aldrich Chemicals). The amino precursors are obtained by deprotecting the corresponding Boc-geminal diamide with trifluoroacetic acid (Houben- Weyl), ibid). The geminal diamide compounds are obtained by coupling the appropriate dipeptide with the mono protected geminal diamine, which in turn is obtained from the N-Cbz-N'-Boc protected diamino precursor by treatment with hydrogen over palladium on carbon. The protected diamine precursor is obtained from commercially available Boc-amino acids via a Hoffman degradation reaction. Some R3 groups may exist as different optical isomers and the present invention includes within its scope each possible optical isomer ie. & or R chiral form. Compounds of formula (I) wherein Rj is benzyloxy or 3-pyridinylmethoxy are prepared from the N,O-dimethylhydroxamide precursor described earlier by hydrogenation over palladium (Houben-Weyl, ibid), followed by acylation with the commercially available chloroformate (Aldrich Chemicals) and reduction with lithium aluminum hydride (Nahm and Weinreb, ibid). Compounds of formula (I) wherein R3 is maleimidomethyl are prepared from the aminomethyl precursor described above by treatment with maleic anhydride, followed by ring-closure with cyanuric fluoride. Compounds of formula (I) wherein R3 is methoxycarbonylglyoxyloyl are prepared from the corresponding tripeptides according to the procedure of Li (Li, Z. et al., J.Med.Chem. 1993, 36, 3472-3480). Compounds odf formula (I) wherein R3 is oxalyi are prepared from their ethylesters (described above) by alkaline hydrolysis under standard conditions. All other compounds of the formula (I) where Rj is not benzyloxy may be prepared from the compound of formula (I) where Rj is H and R3 is dimethoxymethyl by coupling of the corresponding acids according to known procedures (Houben-Weyl, ibid). The required precursor of formula (I) is obtained by deprotection of the previously described compound of formula (1) where R3 is dimethoxymethyl and R\ is benzyloxycarbonyl by hydrogention over palladium (Houben-Weyl, ibid). The required acids are either commercially available or are prepared from commercially available materials (Aldrich Chemicals) by utilising standard peptide coupling procedures (Houben-Weyl, ibid). All R (N-protecting) groups may be introduced by treating the free amino group of the corresponding precursor with either the acid anhydride or acid chloride derivative (Aldrich, Janssen Chemicals) of the respective protecting group in pyridine (Houben- Weyl ibid). The precursors .are obtained from corresponding carbobenzoxy derivatives by hydrogenation or treatment with hydrobromic acid in acetic acid (Houben-Weyl ibid). A further .aspect of the present invention comprises a compound of formula (IV) or a salt thereof: wherein R5' and Rg' may be defined in the same way as R\ above, Rg' and R7' may be defined in the same way as R2 above and X' and Y' may each be carbonylmethylene or methylene. Preferred compounds of formula (IV) according to the invention include those wherein X' and Y' are defined as above, R ' and R7' are indol-3-yl and R5' and Rg' are each independently selected from the group comprising phenyl, benzyl, 2-phenylethyl, benzyloxy, 2-carboxyethyl and methyl and are most preferably benzyloxy. It will be appreciated that all of the compounds of general formula (II) are modified hexapeptides comprising four isoleucine residues and two further amino acid residues, the natures of which are defined by R ' and R7' respectively. Compounds of formula (IV) be prepared by reacting a mixed disulphide with the appropriate methylenethiol (when X' is methylene) or thiomethylketone when X' is carbonylmethylene), containing the desired R5' and Rg' group. When R5' = Rg' the compound is obtained by exposing the corresponding thiol compound (Step 3, Example 57) to air. The mixed disulfide may be obtained by a disulfide exchange reaction between commercially available 2,2'dithiobis(5-nitropyridine) (ibid) and the desired thiol (containing the appropriate R7 and Rg groups). The appropriate methylenethiol or thiomethylketone may be obtained as described for compounds of formula (I). Salts of compounds of formula (I), (III) and (IV) are included within the scope of the invention and include base-addition salts when for example a carboxy group is present and acid-addition salts when for example a heterocyclic aryl group containing a nitrogen is present. Preferred salts of compounds of formula (I), (III) and (IV) are pharmaceutically acceptable salts. All compounds referred to in the description of processes for synthesis of compounds of the present invention should be taken to be in the appropriate chiral form for synthesising the desired enantiomer or mixture of enantiomers. According to the present invention there is also provided a method for the treatment of a cardiovascular disorder and more particularly myocardial infarction, angina pectoris, cerebral infarction (stroke), cerebral vasospasm, ischemic cardiac insufficiency, Raynaud's disease and other vasospastic diseases, atherosclerosis, essential hypertension, pulmonary hypertension, asthma, respiratory distress syndrome, acute renal failure, cyclosporin-induced renal failure, endotoxin shock, endotoxin-induced multiple organ failure, acute failure following organ transplantation, Crohn's disease, ulcerative colitis, gastric ulcer, escleroderma and lupus erythematosus, which comprises the administration to a patient requiring such treatment of a therapeutically effective amount of one or more of a compound or salt or formulation according to the present invention. According to a further feature of the invention there is provided the use of a compound or salt or formulation as defined herein in the manufacture of a medicament for use in therapy of one or more of the cardiovascular disorders described above. According to a further feature of the invention there is provided a pharmaceutical composition which comprises a compound of the present invention, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier. The composition may be in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for nasal use, for example, a snuff, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository; for administration by inhalation, for example as a finely divided powder or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or oily solution or suspension. In general the above compositions may be prepared in a conventional manner using conventional excipients. However, in the case of a composition for oral administration, it may be convenient for the composition to include a coating to protect the peptide active ingredient from the actions of enzymes in the stomach. A preferred composition of the invention is, for example, one suitable for oral administration in unit dosage, for example a tablet or capsule which contains from 2.5 to 500mg, and preferably 2 to 200mg, of peptide in each unit dose to deliver a dose of from 0.05mg/kg to 50mg/kg, or one suitable for parenteral administration which contains from 0.5 to lOOmg of peptide per ml, and preferably 1 to lOmg of peptide per ml of solution, to deliver a dose of from lmg/kg to lOmg/kg bodyweight. A parenteral composition is preferably a solution in isotonic saline or isotonic dextrose buffered if necessary to a pH of 5 to 9. Alternatively, the parenteral composition may be one designed for slow release in which case the amount of polypeptide per unit dose is in general greater than that required when a conventional injectable formulation is used. A preferred slow release formulation is, for example, a continuous release formulation, for example a formulation of the type described in US4767628 and US5004602 which are incorporated herein in their entirety. A preferred slow release parenteral formulation contains from 1O to 100 mg of polypeptide per unit dose. Another preferred slow release formulation is a micro-encapsulated polypeptide using a biodegradable biocompatible copolymer. Example 1 Synthesis of N- -CBZ-S-Amino Acid-N-Methvl-O-Methvl-Hdroxamides: A solution of N-α-CBZ-amino acid-OH (10 mmol), N,O-dimethylhydroxylamine hydrochloride (l lmmol), N-methylmorpholine (12mmol), and 1-hydroxybenzotriazole (12 mmol) in dimethylformamide (50 mL) was treated with l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (llmmol), and the resulting solution was stirred for 12h at 25°C. DMF was removed in vacuo at 40°C. The residue was dissolved in ethyl acetate. The organics were washed successively with 5% NaHCO3- 5% citric acid, and saturated NaCI. The organic phase was then dried with a hyd MgSO4 and was concentrated in vacuo. Compounds were purified by flash chromatography or recrystallization. Example 2 Synthesis of N-ra-Boc-S-Amino Acid-N-Methvl- -Methvl-Hvdroxamides: A solution of Boc-amino acid-OH (3 mmol), N,O-dimethylhydroxylamine hydrochloride (3.1 mmol), 1 -hydroxybenzotriazole (3 mmol), and triethyl-amine (3.1 mmol) in DMF (5mL) was cooled to 0°C. After lOmin, l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (3 mmol) was added, and the reaction proceeded for 18h with gradual warming to 25°C. DMF was removed in vacuao, and the residue was partitioned between 10% Na2CO3 and EtOAc. The aq layer was extracted twice more with EtOAc. The EtOAc fractions were combined and washed with 10% Na2CO3, IN HC1, and saturated NaCl. After drying over anhyd MgSO4, the EtOAc layer was filtered and concentrated in vacuo. Compounds were purified by flash chromatography or recrystallisation. Example 3 Synthesis of HC1-S- Amino Acid-N-Methvl-O-Methvl-Hvdroxamides: Boc-S-amino acid-N-methyl-O-methyl-hydroxamides (*2.5 mmol) were treated with 4N HCl/dioxane (lOmL) for 40 min. Dioxane was removed in vacuo. The residue was triturated twice with ethyl ether. Ether was removed and the products were dried in vacuo in the presence of NaOH(s). Example 4 Synthesis of N-ft-Boc-S-Amino-Acid-S-Amino Acid-N-Methvl-O-Methvl- Hvdroxa ides BOC-amino acid-OH (10 mmol) and HCl-S-aminoacid-N-methyl-O-methyl- hydroxamide (11 mmol) were dissolved in DMF (10 mL). The stirring solution was then cooled to 0°C. After 5 min, diisopropylethylamine (1 lmmol), 1- hydroxybenzotriazole (lOmmol), and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (lOmmol) were added to the flask. The reaction proceeded for 18h with gradual warming to room temperature. DMF was removed in vacuo. and the residue was partitioned between 10% Na2CO3 and EtOAc. The aq.layer was extracted twice more with EtOAc. The EtOAc fractions were combined and washed with 10% Na2CO3, IN HC1, and saturated NaCl. After drying over anhyd MgSO4, the EtOAc layer was filtered and concentrated in vacuo. The products were purified by flash chromatography or recrystallisation. Example 5 Synthesis of H 1 -S-Amino-Acid-S- Amino Acid-N-Methvl-O-Methvl-Hvdroxamides: Synthesis was carried out in the manner described for HCl-S-amino acid-N-Methyl-O- Methyl-hydroxamides using N-α-Boc-S-aιrιino-acid-S-aminoacid-Methyl-O-Methyl- hydroxamides as the starting material. Example 6 Synthesis of N-α-Boc-S-Amino-Acid-S-Amino Acid-S-Amino Acid-N-Methvl-O- Methyl-Hydroxamides ; Synthesis was performed in the manner described for N-α-Boc-S-amino acid-S-amino acid-N-methyl-O-methyl-hydroxamides using a Boc-S-amino acid and HCl-S-amino- acid-S-amino acid-N-methyl-O-methyl-hydroxamides. Example 7 Synthesis of HC1 -S- Amino- Acid-S- Amino Acid-S-Amino Acid-N-Methvl-O-Methvl- Hydroxamides: Synthesis was carried out in the manner described for HCl-S-amino acid-N-methyl-O- methyl-hydroxamides using N-α-Boc-S-amino-acid-S-amino acid-S-amino acid-N- methyl-methyl-hydroxamides as the starting material Example 8 Synthesis of N-α-CBZ-S- Amino Acid-S-Amino Acid-N-Methyl-O-Methyl- Hydroxamides: Synthesis was carried out in the manner described for N-α-CBZ-S-amino acid-N- methyl-O-methyl-hydroxamides using N-α-CBZ-S-amino acid-S-amino acid-OH in place of N-α-CBZ-S-amino acid-OH. Example 9 Synthesis of N-α-CBZ-S-Amino Acid-S-Amino Acid-S-Amino Acid-N-Methvl-O- Methvl-Hvdroxamides: To a solution of N-α-CBZ-S-amino acid-N-methyl-O-methyl-hydroxamide (5 mmol) in methanol (lOOmL) was added 10% Pd/C (50mg). The mixture was stirred for 6h under .an H2 atmosphere using a balloon. After filtration and concentration in vacuo. the white residue was dissolved in DMF (50mL). CBZ-amino acid-amino acid-OH (5mmol, Bachem. Switz.), 1 -hydroxybenzotriazole (5mmol), and l-ethyl-3-(3- dimethylamino-propyl)carbodiimide hydrochloride (5mmol) were added. The solution was stirred for 12h. DMF was removed in vacuo at 40°C. The residue was dissolved in ethyl acetate and was washed with 5% NaHCO3, 5% citric acid, and saturated NaCl . Organics were dried over anhyd MgSO4, filtered, and concentrated in vacuo. A white solid (2,4 g) was obtained. Compounds were purified by flash chromatography or were recrystallised. Exa ple 10 CBZ-amino acid-amino acid-OH (1.32mmol) and HCl-S-amino acid-N-methyl-O- methyl-hydroxamide (1.4mmol) were dissolved in DMF (5mL). The stirring solution was then cooled to 0°C. After 5 min, diisopropylethylamine (1.4mmol), 1- hydroxybenzotriazole (1.32mmol), and 1 -ethyl-3-(3-dimethyl- aminopropyl)carbodiimide hydrochloride (1.32mmol) were added to the flask. The reaction proceeded for 18h with gradual warming to room temperature. DMF was removed in vacuo, and the residue was partitioned between 10% Na2CO3 and EtOAc. The aq layer was extracted twice more with EtOAc. The EtOAc fractions were combined and washed with 10% Na2CO3, IN HCI, and saturated NaCI. After drying over anhyd MgSO4, the EtOAc layer was filtered and concentrated in vacuo. The products were purified by flash chromatography or recrystallisation. Example 1 1 CBZ-amino acid-OH (0.4mmol), HCI-S-amino acid-S-amino acid-methyl-O-methyl- hydroxamide (0.47mmol), 1-hydroxybenzotriazole (0.4mmol), and triethylamine (0.47mmol) were dissolved in DMF (5mL), and the mixture was cooled to 0°C. After 10 min, l-emyl-3-(3-dimethylamino-propyl)carbodiimide (0.4mmol) was added. The reaction proceeded for 18h with gradual warming to 25°C. The reaction was worked up in the manner described in Example 10. Example 12 HCI-S-amino acid-S-amino acid-S-amino acid-N-methyl-O-methyl-hydroxamide (0.66mmol) was suspended in a mixture of chloroform (25mL) and 3N NaOH (12.7mL) at 0°C. To the vigorously stirring solution was added benzyl chloroformate (1.96mmol) dropwise. The reaction proceeded for 18h with gradual warming to 25°C. The reaction mixture was then diluted with DCM (150mL) and H2O (50mL). The organic layer was washed with saturated NaCI, dried over MgSO4, filtered, and concentrated in vacuo to afford the product as an oil. Example 13 To a solution of N-α-CBZ-S-amino acid-S-amino acid-N-methyl-O-methyl- hydroxamide (5mmol) in methanol (150mL) was added 5% Pd/C (200mg). The mixture was stirred for 18h under an H2 atmosphere using a balloon. After filtration and concentration in vacuo. the residue was dissolved in DMF (lOmL). CBZ-amino acid- OH (8.5mmol,), 1-hydroxybenzotriazole (8.5mmol), and l-ethyl-3-(3-dimethylamino- propyl)carbodiimide hydrochloride (8.5mmol) were added. The solution was stirred for 24h. DMF was removed in vacuo at 40°C. The residue was dissolved in ethyl acetate and was washed with IN NaOH, IN HCI, and saturated NaCI. Organics were dried over anhyd MgSO4, filtered, and concentrated in vacuo. A white solid (2.4g) was obtained. Compounds were purified by flash chromatography or were recrystallised. Example 14 Synthesis of N-α-CBZ-S-Amino Acid-S-Amino Acid-S-Amino Acid Aldehydes: THF (lOmL) and 1M lithium aluminum hydride (0.4mmol) were cooled to -50°C with stirring. Next, a solution of N-α-CBZ-S-amino acid-S-amino acid-S-amino acid-μ- methyl-O-methyl-hydroxamide (0.4mmol) in THF (5mL) was added dropwise. The reaction temperataure then climbed to 0°C, and thus temperature was maintained for 4h. During this time, lithium aluminum hydride was added periodically until the reaction was complete by TLC analysis. The reaction mixture was again cooled to -50°C, and the reaction was quenched with 5% citric acid. The mixture was filtered on celite, and the filtrate was combined with EtOAc. The filtrate was then washed with 10% Na2CO3 and saturated NaCI. The organics were dried over MgSO4, filtered, and concentrated in vacuo. Compounds were purified by flash chromatography or recrystallisation. Example 15 N-BenTyloxycarhonyl-S-isoleucvl-S-isoleucine 1 -S-formvl-2-d H-indol- 3-yl]ethylamide: silica gel (10% methanol methylene chloride) H NMR (DMSO) δ: 0.63-0.93 (12H), 0.98-1.8 (4H), 2.62-3.07 (2H), 3.84-4.51 (3H), 5.06 (2H), 6.17-6.21 (IH), 6.31-6.36 (IH), 6.93-7.83 (10H), 8.48-8.52 (IH), 9.47 (IH), 10.63-10.84 (IH) LRMS (El, m/e): 549 (M +1) Anal. (1 H O): C: 65.96, H: 7.60, N: 10.10 2 Example 16 N-Benzyloxycarbonyl-S-isoleucyl-S-isoleucine 1 -S-formyl-2-phenyl- ethylamide: silica gel (10% methanol/methylene chloride) H NMR (DMSO) δ: 0.77 (12H), 1.03 (2H), 1.39 (2H), 1.64 (2H), 2.7-3.1 (2H), 3.90 (IH), 4.22 (IH), 4.36 (IH), 5.02 (2H), 7.1-7.4 (11H), 7.75 (IH), 8.49 (IH), 9.42 (IH) LRMS (EI, m/e): 511 (M+l) Anal. C: 66.21, H: 7.59, N: 8.05 Example 17 N-Benzyloxycarbonyl-S-isoleucyl-S-isoleucine 1 -S-formvl- -methvl- butylamide: silica gel (10% methanol/methylene chloride) H NMR (DMSO) δ: 0.72- 0.9 (18H), 1.0-1.2 (IH), 1.25-1.75 (8H), 3.75-4.23 (3H), 5.03 (2H), 7.35 (5H), 9.37 (IH) LRMS (El, m/e): 476 (M +1) Anal. (1/2 H O): C: 64.49, H: 8.79, N: 8.60 Example 18 N-Benzvloxvcarbonvl-S-is leucvl-S-isoleucine i -S-foπτιvl-2-fben7_o- thien-3-yDethylamide: silica gel (10% methanol/methylene chloride ) H NMR (DMSO) δ: 0.68-0.87 (12), 1.0-1.2 (2H), 1.3-1.8 (4H), 3.0-3.15 (2H), 3.88-4.0 (IH), 4.2-4.28 (IH), 4.49-4.62 (IH), 5.0-5.05 (2H), 7.28-7.48 (10H), 7.79-7.89 (IH), 7.92- 8.03 (IH), 9.54 (IH) LRMS (El, m/e): 566 (M +1) Anal. (1/2 H O): C: 64.32, H: 7.18, N: 7.26 Example l9 N-Benzvloxvcarhonvl-S-p-bromophenvlalnvl-S-rO-benzvntvrosvl-l-S-formvl-l -nH- indol-3-yl-methylVmethylamide: IH NMR (δ, DMSO-d 6 ): 2.6-3.2 (6H), 4.2-4.6 (3H), 4.8-5.1 (4H), 6.9-7.6 (24H), 8.2 (IH), 8.6 (IH), 9.4 (IH), 10.9 (IH) Example 20 N-Benzyloxycarbonyl-S-phenylalanyl-S-isoleucyl-1 -S-formyl- 1 -CSV 1- methylpropylmethylamide: IH NMR (δ, CDC1 3 ): 0.8-1.1 (12H), 1.2-1.6 (4H), 1.9 (IH), 2.1 (IH), 3.1 (2H), 4.3 (IH), 4.4-4.6 (2H), 5.1 (2H), 5.2 (IH), 6.4 (2H), 7.2 (10H), 9.6 (IH) LRMS (FAB): 510.4 (MH + ) Example 21 N-Benzvloxvcarbonvl-S-alanvl-S-phenvla1anvl-l -S-foπτιvl-1 -f2-S-hιιtvn-methvlamide: IH NMR (δ, CDCI3): 0.9 (6H), 1.3 (5H), 2.0 <1H), 3.1 (2H), 4.2 (IH), 4.4 (IH), 4.7 (IH), 5.1 (3H), 6.4 (IH), 6.6 (IH), 7.2-7.4 (10H), 9.5 (IH) LRMS (FAB): 468.2 (MH + ) Example 22 N-Benzyloxycarhonyl-S-isoleucyl-S-isoleucyl-l -S-formvl-1 -fSVl -methvlpropvlV methylamide: IH NMR (δ, CDCl 3): 0.8-1.3 (21H), 1.3-1.6 (3H), 1.7-2.1 (3H), 4.2 (IH), 4.4 (IH), 4.6 (IH), 5.1 (2H), 5.7-6.0 (IH), 7.0-7.2 (IH), 7.3 (6H), 9.6 (IH) LRMS (FAB): 476.2 (MH + ) Example 23 N-Benzyloxycarhonyl-S-isoleucvl-S-phenvlalanvl-l-S-formvl-l-rSVl- methylpropylbutyl-methylamide: IH NMR (δ, CDCl 3): 0.8-1.0 (12H), 1.0-1.4 (4H), 1.8-2.0 (2H), 3.1 (2H), 4.0 (IH), 4.4 (IH), 4.7 (IH), 5.1 (2H), 5.2 (IH), 6.5 (2H), 7.2- 7.4 (10H), 9.5 (IH) LRMS (FAB) 510.3 (MH + ) Example 24 N-Benzvloxvcarbonvl-S-valvl-S-isoleucvl-l-S-formvl-l-πH-indo-3-vl-methvl- ethylamide: 1H NMR (δ,DMSO-d 6 ): 0.6-1.0 (12H), 1.0-1.5 (2H), 1.7 (IH), 2.0 (IH), 3.0-3.3 (2H), 3.9 (IH), 4.3 (IH), 4.5 (IH), 5.0 (2H), 7.0-7.4 (10H), 7.5 (IH), 7.8 (IH), 8.5 (IH), 9.5 (IH), 10.9 (IH) LRMS (FAB): 535.5 (MH+) Example 25 N-Benzyloxycarbonyl-S-phenylalanvl-S-isoleucvl-1 -S-formvl-1 -fl H-indol-3-vl- methylVmethylamide: IH NMR (δ, DMSO-d 6 ): 0.6-1.0 (6H), 1.0-1.8 (3H), 2.6-3.2 (4H), 4.2-4.5 (3H), 5.0 (2H), 7.0-7.6 (16H), 7.9 (IH), 8.5 (IH), 9.5 (IH), 10.9 (IH) LRMS (FAB): 583.6 (MH + ) Example 26 N-Benzyloxycarbonyl-S-alanvl-S-phenvlalanvl-1 -S-foπnvl-1 -H H-indol-3-vl-methvl V methylamide: IH NMR (δ, DMSO-d 6 ): 1.1 (3H), 2.6-3.3 (4H), 4.1 (IH), 4.4 (IH), 4.6 (1H), 5.0 (2H), 7.0-7.6 (16H), 8.0 (IH), 8.5 (IH), 9.4 (IH), 10.9 (IH) LRMS (FAB): 541.2 (MH + ) Example 27 N-Benzvloxvcarhonvl-S-isoleucvl-S-phenvlalanvl-1 -S-formvl-1 -Cl H-indol-3-vl- methylVmethylamide: 1H NMR (δ, DMSO-d 6 ): 0.7 (6H), 1.0 (IH), 1.3 (IH), 1.6 (IH), 2.7-3.3 (4H), 3.9 (IH), 4.4 (IH), 4.7 (IH), 5.0 (2H), 7.0-7.4 (15H), 7.5 (IH), 8.1 (IH), 8.5 (IH), 9.5 (IH), 10.9 (IH) LRMS (FAB): 583.3 (MH + ) Example 28 N-Benzvloxvcarhonvl-S-leucvl-S-isoleucvl-1 -S-formvl-1 -d H-indol-3-vl-τnethvl- methylamide: IH NMR (δ, DMSO-d 6 ): 0.8 (12H), 1.1 (IH), 1.4 (3H), 1.7 (2H), 2.9-3.3 (2H), 4.1 (IH), 4.3 (IH), 4.4 (IH), 5.0 (2H), 7.0-7.6 (11H), 7.7 (IH), 8.5 (IH), 9.5 (IH), 10.9 (IH) LRMS (FAB): 549.5 (MH + ) Example 29 N-Benzvloxvcarhonvl-S-isoleucvl-S-valvl-1 -S-formvl-1 -(\ H-indol-3-vl-methvlV methylamide: lH NMR (δ, DMSO-d 6 ): 0.6-1.0 (12H), 1.1 (IH), 1.4 (IH), 1.7 (IH), 2.0 (IH), 3.0-3.3 (2H), 4.0 (IH), 4.3 (IH), 4.5 (IH), 5.0 (2H), 7.0-7.4 (10H), 7.5 (IH), 7.8 (IH), 8.5 (IH), 9.5 (IH), 10.9 (IH) LRMS (FAB): 535.4 (MH + ) Example 30 N-Benzyloxvcarhonvl-S-isoleucvl-S-trvptophanvl-l-S-formvl-l-πH-indol-3-vl- methvn-methylamide: IH NMR (δ DMSO-d 6 ): 0.6-1.1 (8H), 1.6 (IH), 2.8-3.2 (4H), 3.9 (IH), 4.3 (IH), 4.6 (IH), 5.0 (2H), 6.9-7.6 (16H), 8.0 (IH), 8.5 (IH), 9.3 (IH), 10.8 (2H) LRMS (FAB): 622.5 (MH + ) Exampte 31 N-Ben2yloxycarbonyl-S-tιvptophanvl-S-trvptophanvl-l-S-formvl-l-riH-indol-3-vl- methylVmethylamide: IH NMR (δ DMSO-d 6 ): 2.8-3.3 (6H), 4.3 (2H), 4.7 (IH), 5.0 (2H), 6.9-7.7 (21H), 8.2 (IH), 8.5 (IH), 9.3 (IH), 10.8 (3H) LRMS (FAB): 695.7 (MH+) Example 32 N-Benzyloxycarhonyl-S-phenvlalanvl-S-phenvlalanvl-l -S-formvl-l -π H-indol-3-vl- methylVmethylamide: IH NMR (δ, DMSO-d 6 ): 2.6-3.3 (6H), 4.3 (2H), 4.7 (IH), 5.0 (2H), 7.0-7.6 (21H), 8.2 (IH), 8.6 (IH), 9.4 (IH), 10.9 (IH) LRMS (FAB): 617.3 (MH + ) Example 33 N-Benzvloxvcarbonvl-S-isoleucvl-S-isoleucvl-l-S-formvl-l- -hvdroxy-benzylV methylamide: IH NMR (δ, DMSO-d 6 ): 0.8-1.0 (14H), 1.2-1.4 (2H), 1.5-1.8 (2H), 2.6 (IH), 3.0 (IH), 3.9 (IH), 4.2 (2H), 5.0 (2H), 6.6 (2H), 6.9 (2H), 7.3 (6H), 7.7 (IH), 8.4 (IH), 9.2 (IH), 9.4 (IH) LRMS (FAB): 526.4 (MH+) Anal.C: 65.21, H: 7.57, N: 7.76 Example 34 N-Benzyloxycarbonvl-S-trvptophanvl-S-l 'naphthvlalanvl-1 -S-formvl-1 -( 1 H-indol- -vl- methylVmethylamide: IH NMR (δ, DMSO-d 6 ): 2.8-3.6 (6H), 4.2-4.5 (2H), 4.7-5.1 (3H), 6.9-8.0 (22H), 8.2 (IH), 8.3 (IH), 8.5 (IH), 9.4 (IH), 10.8 (IH), 10.9 (IH) LRMS (FAB): 706.3 (MH + ) Example 35 N-Ren7yloxycarhonyl-S-trvptophanyl-S-2'naphthvlalanvl-l -S-formvl-l -fl H-indol-3-vl- ethylVmethylamide: IH NMR (δ, DMSO-d 6 ): 2.7-3.5 (6H), 4.2 (IH), 4.4 (IH), 4.7 (1H), 4.9 (2H), 6.9-7.9 (23H), 8.2 (IH), 8.6 (IH), 9.4 (IH), 10.7 (IH), 10.9 (IH) LRMS (Ion Spray): 765.3 (MH + ) Example 36 N-BenTvloxycarbonyl-S-trvptophanvl-S-C -henzvntvrosvl-l -S-formvl-l -π H-indol-3- yl-methylVmethylamide: IH NMR (δ, DMSO-d 6 ): 2.7-3.3 (6H), 4.3 (2H), 4.6 (IH), 5.0 (4H), 6.6-7.7 (25H), 8.0 (IH), 8.6 (IH), 9.4 (IH), 10.8 (IH), 10.9 (IH) LRMS (Ion Spray): 779.4 (M+NH 4 + ) Example 37 N-Ben7vloxvcarhonv1-S-p-hromophenvlalanvl-S-l 'naphthvlalanvl-1 -S-formvl-1 -π H- indol-3-yl-methylVmethylamide: IH NMR (δ DMSO-d 6 ): 2.5-3.5 (6H), 4.2-4.4 (2H), 4.7 (IH), 4.9 (2H), 6.9-7.6 (19H), 7.8 (IH), 7.9 (IH), 8.1 (IH), 8.4 (IH), 8.6 (IH), 9.4 (IH), 10.8 (IH) LRMS (FAB): 745.2, 747.2 (MH + Example 38 N-Ben7vloxvcarhonv1-S-p-bromophenvlalanvl-S-2'naphthvlalanvl-l -S-formvl-1 -π H- indol-3-yl-methylVmethylamide: IH NMR (δ,DMSO-d 6 ): 2.6-3.3 (6H), 4.3 (IH), 4.4 (IH), 4.7 (IH), 4.9 (2H), 7.0-7.9 (22H), 8.3 (IH), 8.6 (IH), 9.5 (IH), 10.9 (IH) LRMS (Ion Spray): 799.5 (M+Na+MeOH) Example 39 N-Benzyloxycarhonyl-S-1 'naphthylalanyl-S-fO-benzvl ιtvrosvl-1 -S-formvl-l -C4- chlorophenylmethylVmethyloamide: IH NMR (δ, DMSO-dg): 2.7-3.2 (6H), 4.2-4.4 (2H), 4.9 (2H), 5.0 (IH), 5.1 (2H), 6.9-8.2 (27H), 8.6 (IH), 9.4 (IH) LRMS (Ion Spray): 768.3 (MH+) Example 40 N-Benzyloxycarbonyl-S-p-iodophenylalanyl-S-rnaphthylalanyl-l-S-formyl-l-dH- indol-3-yl-methylVmethylamide: IH NMR (δ, DMSO-d 6 ): 2.6-3.3 (6H), 4.3 (2H), 4.8 (IH), 5.0 (2H), 6.6-8.0 (21H), 8.2 (IH), 8.4 (IH), 8.6 (IH), 9.4 (IH), 10.8 (IH), 4.8 (IH) LRMS (FAB): 793.2 Example 41 N-Ben7vloxvcarbonvl-L-isoleucvl-L-isoleucine-L-N-[1-acrvlovl-2-πH-indol-3- vnethvηamide: A solution of 1.2g (2mMol) of Z-lle-lle-Trp-N-methyl-N- methoxyamide (see above), in lOmL of tetrahydrofuran was cooled to -78° and treated with 22mL (22mMol) of vinylmagnesium bromide (IM in THF). The reaction mixture was allowed to warm to 25° and was stirred at that temperature for 24h. The resulting mixture was poured into excess IN hydrochloric acid and extracted with ethylacetate. Evaporation of the solvent followed by chromatography on silica gel (1:1 hexanes/ethyl acetate) and trituration with ether afforded the desired vinyl ketone as a white solid (0.4g 1st crop, 0.3g 2nd crop). 1H-NMR (CDCl 3): δ 0.79 (12H), 1.02 (2H), 1.28 (2H), 2.70 (2H), 3.02 (2H), 3.92 (IH), 4.22 (IH), 4.83 (IH), 5.01 (2H), 5.78 (IH), 6.19 (IH), 6.50 (IH), 6.96 (IH), 7.02 (IH), 7.08 (IH), 7.30 (7H), 7.5 (IH), 7.78 (IH), 8.41 (IH), 10.80 (IH). LRMS:(FAB):575 (M++1) Anal.:C,H,N. Example 42 N-Benzyloxvcarhonvl-L-isoleucvl-L-isoleucine-L-N-[l-acryloyl-2-rphenyl ιethyl]amide This compound was obtained using the procedure employed in Example 41, starting with the corresponding Cbz-llellePhe amide precursor 1H-NMR (DMSO d 6 ) 0.78(12H), 1.04(2H), 1.38(2H), 1.66(2H), 2.80(1H), 3.00(1H), 3.92(1H), 4.21(1H), 4.79(1H), 5.01(2H), 5.80(1H), 6.22(1H), 6.56(1H), 7.1-7.4(1 IH), 7.7(1H), 8.4(1H) LRMS (FAB): 536.5 (M+l) Anal: C,H,N Example 43 N-Benzyloxycarbonyl-I.-isoleucvl-L-i.soleucine- -N- l -π-hvdroxvallvlV2- (phenyl ethyl]amide: A suspension of 3.6g (6.6mMol) of the vinyl ketone obtained in Example 42 in 300 mL of methanol was treated with 3.6g (lOmMol) of cerium-III- chloride heptahydrate and then cooled on an ice-bath. 0.5g (13.5mMol) of sodium borohydride was added scoopwise over 10 minutes and the resulting mixture was stirred for lh and then quenched with saturated aqueous ammonium chloride solution. Extraction with chloroform, drying over magnesium sulfate and removal of the solvent in vacuo. followed by trituration with ether afforded the desired allylic alcohol (3.2g) as a white solid and as a mixture (approximately 1:1) of diastereomers. 1H-NMR (DMSO d 6 ): 0.83(12H), 1.00(2H), 1.38(2H), 1.83(2H), 2.60(1H), 2.82(2H), 3.85-4. 15(3H), 5.00(3H), 5.20(1H), 5.82(2H), 7-7.4(10H), 7.6(1H), 7.7(1H). LRMS (FAB): 539 (M++1) Anal: C,H,N Example 44 N-Benzvloxvcarbonvl-L-isoleucvl-L-isolencine-L-N-fl-[l-hvdroxvπ-oxiranvl .methvl- 2-(phenyπethyllamide A solution of 0.5g (0.93mMol) of the allylic alcohol obtained in Example 43, in 300mL of 1:1 chloroform-methanol was treated with 8g of m- chloroperbenzoic acid at 25°. The resulting mixture was stirred for 8h and extracted with IN sodium hydroxide solution. Drying over magnesium sulfate and removal of the solvent in vacuo. followed by trituration with 10% tetrahydrofuran-ether, afforded the desired epoxide (0.4g) as a mixture of four diastereomers. 1H-NMR (DMS0 d 6 ): 0.78(12H), 1.05(2H), 1.38(2H), 1.70(2H), 2.58(2H), 2.72(1H), 2.90(2H), 3.08(1H), 4.15(2H), 5.05(2H), 7.1-7.4(10H), 7.6(1H), 7.75(1H) LRMS (FAB): 555 Anal: C,H,N Example 45 N-Ben7yloxycarhonyl-T,-isoleucyl- -isoleucine-L-N-[l-[2-oxiranvlcarbonvl]-2- (phenyltethyl]amide A solution of O.lg (0.18mMol) of the epoxide obtained in Example 44, in 5mL of dimethylsulfoxide and ImL of acetic anhydride was stirred at 25 ° for 3 days. The resulting mixture was poured into water and centrifuged. The solids were collected and triturated with ether to afford the desired ketoepoxide as a white solid (0.05g) as a mixture of two diastereomers (-1:1). 1H-NMR (DMSO d^) 0.78(12H), 1.03(2H), 1.38(2H), 1.65(2H), 2.80(2H), 2.95(1H), 3.16(1H), 3.66(1H), 3.92(1H), 4.20(1H), 4.70(1H), 5.02(2H), 7.2-7.4(10H), 7.7(1H), 8.58(1H) LRMS (FAB): 553 (M+l) Anal: C,H,N Example 46 N-Benzyloxycarbonyl-L-isoleucyl-L-isoleucine-L-N-[l-glvoxyloyl-2- fphenyπethyl]amide: A solution of l.Og (1.8mMol) of the vinylketone obtained in Example 42, in 400mL of 4:1 Chloroform-methanol was cooled to -78° and treated with a stream of ozone until a blue color was observed. The resulting mixture was treated with lOmL of dimethylsulfide and allowed to warm to 25°. The volatiles were evaporated in vacuo and the residue was triturated with 10% tetrahydrofuran-ether to give the desired ketoaldehye (0.75g) as a pale yellow solid). 1H-NMR (DMSO d 6 ) 0.75(12H), 1.05(2H), 1.38(2H), 1.65(2H), 2.85(2H), 3.85(1H), 4.18(2H), 5.00(3H), 7-7.4(10H), 7.6(1H), 8.7(1H) LRMS (FAB): 539 (M+l) Anal: C,H,N Example 47 N-Ben7yloxycarbonyl-L-isoleucvl-I.-isoleucine-L-N- l-formvlhvdroxvmethvl-2- (phenylethyljamide.: 15g of the allylic alcohol obained in Example 43 was treated in an identical fashion to the procedure outlined in Example 46 to give the desired aldehyde (0.12g) as a white solid and as a 1 : 1 mixture of diastereomers. 1H-NMR (DMSO d 6 ) 0.72(12H), 1.02(2H), 1.39(2H), 1.63(2H), 2.70(1H), 2.82(1H), 3.30(1H), 3.95(2H), 4.20(2H), 5.00(2H), 5.6 and 6.8(1H), 7-7.4(10H), 7.6(1H), 7.8- 8.1(1H),9.42(1H) LRMS(FAB):541(M+1) Anal.: C,H,N Example 48 N-Benzvloxvcarhonvl-L-isoleucvl-L-isoleucine-L-N- 1 [3-ftrimethvlsilv1]-2- propynoyl]2-dH-indol-3-yπethyl]amide: A solution of 2.8g (20mMol) of trimrthylsilylacetylene (Aldrich Chemicals) in 1 OmL of tetrahydrofuran was cooled to - 78° and treated with 13.3mL of 1.5n n-butyllithium. The resulting solution was stirred at -78° for 10 min and then treated with 1.2g (2mMol) of the N,O- domethylhydroxamide of Cbz-llelle Tip described above. The mixture was stirred for lh and then allowed to warm to 25° over 2h. Saturated aqueous amonium chloride was added and the volatitles were removed in vacuo. The residue was chromatographed on silica gel with 75% ethyl acetate -hexane to give the desired propargyl ketone as a beige solid (0.15g). 1H-NMR (CDC1 3 ) 0.21(9H), 0.81(12H), 1.15(2H), 1.40(2H), 1.80(2H), 3.40(2H), 3.98(1H), 4.28(1H), 5.01(1H), 5.05(2H), 5.23(1H), 6.38(1H), 6.99(1H), 7.18(1H), 7.19(1H), 7.38(7H), 7.60(1H), 8.22(1H) LRMS (FAB): 645 (M+l) Anal: C,H,N Example 49 N-Benzyloxvcarhonvl-L-isoleucvl-L-isoleucine-L_N-[l[2-propvnovl]2-πH-indol-3- yπethyl]amide: A solution of the silylated compound described in Example 48 (0.05g, 0.08mMol) in ImL of methanol was treated with O.lmL of saturated aqueous sodium bicarbonate. The resulting mixture was evaporated and chromatographed on silica gel with 35% ethylacetatehexanes to give the desired propargyl ketone as a pale beige solid (0.03g). 1H-NMR (CD 3 0D 0.6-0.8(12H), 1.10(2H), 1.40(2H), 1.6-1.8(2H), 3.17(1H), 3.40(1H), 3.95(1H), 4.00(1H), 4.21(1H), 4.80(1H), 5.03(2H), 7.0-7.4(10H) LRMS (FAB): 573 (M+l) Anal.: C,H,N Example 50 N-Benzyloxycarbonyl-L-isoleucyl-L-isoleucine-L-N-[l-dimethoxymethyl-2-dH-indol- 3-yπethyl]amide: A solution of 0.25g (0.47mMol) of the aldehyde compound obtained in Example 15, in 3mL of methanol and ImL of trimethylorthofor ate was treated with 0.05g of pyridinium p-toluenesulfonate. The resulting mixture was stirred at 25° for 12h and the volatiles were removed in vacuo. The residue was partitioned between ethyl acetate and IN hydrochloric acid and the organic layer was washed with saturated aqueous sodium bicarbonate. Drying over magnesium sulfate, removal of the volatiles in vacuo and trituration with ether afforded the desired acetal as a white solid (0.2g) lH-NMR (DMSO d 6 ) 0.78(12H), 1.05(2H), 1.38(2H), 1.70(2H), 2.77(1H), 2.92(1H), 3.28(3H), 3.31(3H, 3.95(1H), 4.20(3H), 5.01 (2H), 6.95(1H), 7.02(2H), 7.25-7.4(7H), 7.48(1H), 7.7(1H), 7.8(1H), 10.72(1H) LRMS (FAB): 596 (M+l) Anal.: C,H,N Example 51 N-Benzvloxvcarbonvl-I--iso]eucvl-L-isoleucine-L-N-rrEV2-fmethoxvcarhonvl invl]2- dH-indol-3-yπethyl]amide: A solution of 5.0g (27mMol) of trimethylphosphonoacetate (Aldrich Cemicals) in 50mL of tetrahydrofuran was treated with 0.3g (12.5mMol) of sodium hydride. The resulting thick slurry was stirred at 25° for 0.5h and then treated with a solution of 0.5g (lmMol) of Cbz-llelleTrp aldehyde described in Example 15, in lOmL if tetrahydrofuran. The resulting mixture was stirred at 25° for lh and diluted with ethylacetate. Extraction with saturated ammonium chloride solution, drying over magnesium sulfate and removal of the solvent in vacuo, followed by a plug-filtration on silica get (35% ethylacetate-hexanes) afforded the desired ester as a 5:1 mixture of trans:cis isomers and as a white solid (0.4g). lH-NMR (DMSO d 6 ) 0.75(12H), 1.05(2H), 1.38(2H), 1.70(2H), 2.94(2H) 3.95(0.8H,trans), 4.00(0.2H,cis), 4.15(0.2H,cis), 4.18(0.8H,trans), 4.78(1H), 5.02(2H0, 5.79(0.2H,cis), 5.82(0.8H,trans), 6.1 l(0.2H,cis), 6.87(0.8H,trans), 6.92(1H), 7.08(1H), 7.14(1H), 7.3(7H), 7.51(0.8H), 7.57(0.2H) LRMS (FAB): 606 (M+l) Anal. C,H,N Example 52 N-Ben7vloxycarhonvl-L-isoleucvl-L-isoleucine-L-N-[1pvruvovl]2-Cphenvnethvl]amide: Step 1 : A solution of 15mL (~150mMol) of ethylvinylether (Aldrich Chemicals) in 50mL of tetrahydrofuran was cooled to -78° and treated with 75mL (130mMol) of 1.7M tert-butyllithium in hexanes. The resulting mixture was warmed to -40° and cooled back to -78° and then treated with a solution of 8.0g (15mMol) of Cbz-llellePhe-N,O- dimethylhydroxamide (described above) in lOmL of tetrahydrofuran. The reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. Drying over magnesium sulfate and removal of the volatiles in vacuo, followed by recrystallisation from tetrahydrofuran afforded the enolether intermediate (4.6g) as a white solid. Step 2: A solution of 0.75g (1.3mMol) of the enolether of Step 1 in 50mL of tetrahydrofuran was treated with 5mL of concentrated hydrochloric acid. The resulting mixture was stirred for 4h at 25° and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo. Trituration with 10% tetrahydrofiiran-ether afforded the desired ketocarbonyl compound as a white solid (0.55g). lH-NMR (DMSO-d 6 ): enolether Step 1 : 0.78(12H), 1.05(2H), 1.38(2H), 1.65(2H), 2.72(1H), 2.98(1H), 3.77(2H), 3.85(1H), 4.22(1H), 4.62(1H), 5.02(2H), 5.17(1H), 5.19(1H), 7.2-7.4(1 IH), 7.62(1H), 8.25(1H), Step 2: 0.78(12H), 1.05(2H), 1.38(2H), 1.68(2H), 2.18(3H), 2.80(1H), 3.08(1H), 3.93(1H), 4.20(1H), 4.86(1H), 5.02(2H), 7.15-7.4(1 IH), 7.75(1H), 8.78(1H), LRMS (FAB): enolether Step 1: 581 (M+l) Step 2: 553 (M+l) Anal.: Step 1 : C,H,N Step 2: C,H.N. Example 53 N-Benzyloxycarhonyl-I.-isoleucyl-L-isoleucine-L-N-[l-ethoxalvl]2- (phenyl thyl]amide: A solution of 2.0g (3.6mMol) of the enolether intermediate described in step 1 of Example 52, in 130mL of chloroform-methanol (4:1) was cooled to -78° and a stream of ozone was passed through the mixture for 5 minutes. 1 OmL of dimethylsulfide were added and the mixture was allowed to warm to 25°. The volatiles were evaporated in vacuo and the residue was recrystallised from 10% tetrahydrofiiran- ether to afford the desired ester as a white solid (1.25g). lH-NMR )DMSO-d 6 ): 0.75(12H), 1.10(2H), 1.18(3H), 1.38(2H), 1.62(2H), 2.85(1 H), 3.13(1H), 3.92(1H), 4.18(2H), 4.25(1H), 5.00(1H), 5.02(2H), 7.15-7.4(1 IH), 7.72(1H), 8.65(1H). LRMS (FAB): 583 (M+l) Anal.: C,H,N Example 54 N-Benzvloxvcarhonvl-L-isoleucvl-L- soleucine-L-N-[l {2-chloroacetvl]2-dH-indol-3- yπethyl]amide: Step 1 Boc-Trp-chloromethylketone: A solution of 45g (150mMol) of Boc-Tryptophan (Bachem Bioscience) in 500mL of tetrahydrofuran was treated with 24.3mL of triethylamine and cooled to 0°, 16.7mL (175mMol) of ethylchloroformate was added dropwise, the resulting mixture was stirred for 2h at 0° and then filtered. The filtrate was cooled back to 0° and treated with ~250mMol of diazomethane in ether, stirred for 2h and then treated with 36mL of 4M hydrogen chloride in dioxane. After stirring for lh, the volatiles were removed in vacuo and the residue was partitioned between ether and saturated aqueous sodium bicarbonate. Drying over magnesium sulfate, removal of the solvent in vacuo and chromatography on silica gel (40% ethyl acetate-hexanes) afforded the desired chloromethylketone (lOg) as a white solid. Step 2: 1.7g (5mMol) of the chloromethylketone from step 1 were treated with 50mL of 4M hydrogen chloride in dioxane. The mixture was stirred for 0.5h and the volatiles were removed in vacuo. In a seperate flask, a solution of 1.25g (3.3mMol) of Cbz-llelle (Bachem Biosciences) in lOmL of tetrahydrofuran and 0.487mL of triethylamine was cooled to 0° and treated with 0.333mL (3.5mMol) of ethylchloroformate. The mixture was stirred for lh at 0°, filtered and treated with a solution of the residue of flask 1 in 10ml of tetrahydrofuran. 0.3mL of triethylamine were added and the resulting mixture was stirred for 12h at 25°. Dilution with ethylacetate and extraction with IN hydrochloric acid and saturated aqueous sodium bicarbonate, followed by drying over magnesium sulfate, removal of the solvent in vacuo and chromatography on silica gel (ethylacetate) afforded the desired compound as a beige solid (0.4g). IH-NMR Step 1 (CDCI3): 1.38(9H), 3.21(2H), 4.02(2H), 4.77(1H), 5.18(1H), 7.00(1H), 7.18(1H), 7.20(1H), 7.38(1H), 7.61(1H), 8.18(1H). Step 2 (DMSO-d 6 ) 0.78(12H), 1.05(2H), 1.38(2H), 1.70(2H), 3.00(1H), 3.18(1H), 3.95(1H), 4.20(1H), 4.22(1H), 4.65(1H), 5.00(2H), 6.97(1H), 7.00(1H), 7.14(1H), 7.23(6H), 7.44(1H), 7.63(1H), 8.38(1H), 10.65(1H) LRMS (FAB Step 1 : 338 (M+l) Step 2: 599 (M+l) Anal: Step 1 : C,H,N,CI Step 2: C,H,N,CI Example 55 N-Benzvloxvcarhonvl-L-isoleucvl-L_isoleucine-L-N-π [2-(acetvlthio>acetvl]2- phenyl thyl] amide : A solution of 0.5g (0.9mMol) of Cbz-llellePhe- chloromethylketone (prepared in an identical fashion as outlined for Cbz-llelleTrp- chloromethylketone in Example 54) in 2mL of tetrahydrofuran and 3mL of methanol was purged with nitrogen and treated with l.Og (8.9mMol) of potassiumthioacetate. The mixture was stirred for 12h and diluted with ethyl acetate. Extraction with saturated aqueous sodium bicarbonate, followed by drying over magnesium sulfate, removal of the solvent in vacuo and chromatography on silica gel (1% ethanol/dichloromethane) afforded the desired compound as a white solid (O.lg). IH-NMR (DMSO-d 6 ): 0.80(12H), 1.05(2H), 1.40(2H), 1.65(2H), 2.38(3H), 2.80(1H), 3.18(1H), 3.92(1H), 3.98(2H), 4.20(1H), 4.68(1H), 5.02(2H), 7.1-7.4(1 IH), 7.80(1H), 8.50(1H) LRMS (FAB): 598.7 (M+l) Anal.: C,H,N.S Example 56 N-Benzyloxycarbonyl-L-isoleucyl-T.-isoleucine-L-N-[l [semicarbazonomethvl]2-dH- indol-3-vπethyl]amide: A solution of the aldehyde compound obtained in Example 15 (5g) in lOOmL of ethanol was treated with a solution of 2g of semicarbazide hydrochloride and 1.5g of sodium acetate in 50mL of water. The resulting mixture was refluxed for 2h, cooled and diluted with 300mL of water. Extraction with ethylacetate and evaporation of the volatiles in vacuo. followed by recrystallisation from aqueous ethanol afforded the semicarbazone (2g) as a white solid. LRMS (FAB): 607 (M+l) Anal.: C.H,N Example 57 N-rbenzvloxv')carbonvl-L-isoleucvl-L-isoleucine- -N[l-[[('5-nitro-2- pvridvndithiolmethvl]-2-dH-indol-3-vnethyl]amide: Step 1 : A solution of 20g (69mMol) of Boc-tryptophanol (Bachem Biosciences) and 11.2mL of triethylamine in 400mL of dichloromethane was treated with 8.8g (77mMol) of methanesulfonyl chloride at 25° over 0.5h. The resulting mixture was extracted with IN aqueous hydrochloric acid and saturated aqueous sodium bicarbonate dried over magnesium sulfate and concentrated in vacuo. Recrystallisation from dichloromethane-hexanes afforded the desired mesylate (22. lg) as a white solid. Step 2: A solution of 9.0g (24mMol), of the mesylate from Step 1 and 3.5g (31mMol) of potassium thioacetate in lOOmL of acetonitrile was stirred for 12h at 25° and then heated to 50° for 0.5h. the reaction was diluted with ether and extracted with water. Drying over magnesium sulfate and removal of the solvent in vacuo. followed by chromatography on silica gel (20% ethylacetate/hexane) gave the desired thioacetate (5.7g) as a beige solid. Step 3: A solution of 1.5g (6.6mMol) of the thioacetate from Step 2 in 50mL of 2M ammonia in methanol was stirred at 25° for 12h. the volatiles were removed in vacuo and the residue was dissolved in 50mL of 4M hydrogen chloride in 1,4-dioxane. The resulting solution was stirred at 25° for 2h and then concentrated in vacuo to give a brown foam, which was redissolved in 25mL of dimethylformamide and treated with 3.4g (9mMol) of Cbz-isoleucylisoleucine (Bachem Biosciences), 1.3g (9mMol) of hydroxybenzotriazole, 1.7g (9mMol) of EDCI and l .Og (9mMol) of triethylamine. The resulting mixture was stirred at 25° for 12h and then concentrated in vacuo. The residue was partitioned between ethylacetate and IN aqueous hydrochloric acid, the organic layer was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo. Chromatography on silica gel (15% tertbutyl- methylether-dichloromethane) afforded the desired thiol (0.55g) as a beige foam and the corresponding disulfide (0.3g) as a pale yellow solid. Step 4: A solution of 0.25g (0.42mMol) of the thiol obtained in Step 3 and 0.39g (1.25mMol) of 5,5'dinitro-2,2'-dithiobispryidine (Aldrich) in 5mL of dimethylformamide was treated with 0.2g of 4-dimethylaminopyridine and stirred at 25° for 5 days. The volatiles were removed in vacuo and the residue was chromatographed on silica gel (50% ethylacetate-hexane) to give the desired disulfide (0.05g) as a yellow solid IH-NMR Step 1 : (CDCl 3) 1.42(12H), 3.98(3H), 3.05(2H),4.20(3H), 4.80(1 H), 7.1-7.3(4H), 7.4(1H), 7.58(1H), 8.12(1H) Step 2: (CDC1 3 ) 1.42(12H), 2.37(3H), 2.98(2H), 3.08(2H), 4.10(1H), 4.73(1H), 7- 7.4(4H), 7.65(1H), 8.27(1H) Step 3: (DMSO-dό) 0.78(12H), 1.07(2H), 1.40(2H), 1.70(2H), 2.19(1H), 2.58(1H), 2.80(2H), 3.02(1H), 3.9-4.2(3H), 4.99(2H), 6.9-8(14H), 10.80(1H), Step 4: (CD3OD) 0.85(12H), 1.18(2H), 1.55(2H), 1.82(2H), 2.88 (2H), 3.02(2H), 3.99(1H), 4.22(1H), 4.50(1H), 5.07(2H), 6.92(1H), 7.00(2H), 7.2-7.4(7H), 7.55(1H), 7.72(1H, 8.25(1H), 9,00(1H) LRMS Step 1 : 369, Step 2: 349, Step 3: 568 Step 4: 722 Anal.: Step 1 : C,H,N,S Step 2: C,H,N,S Step 3: C,H,N,S Step 4: C,H,N,S Example 58 N--r3.3-diphenylpropionvlVL-isoleucvl-T.-isoleucine-L-N-fl-formvll2-dH-indol-3- ynethyljamide: Step 1 : A solution of 1.9g (3.2mMol) of the compound of formula (I) where R3 is dimethoxymethyl (Example 50), in 200mL of methanol was treated with O.lg 5%palladium on carbon and then stirred under an atmosphere of hydrogen gas for 0.5h. The mixture was filtered through a layer of Celite and the volatiles were removed in vacuo to give the free amine as a white solid (1.2g). Step 2: A solution of 0.23g (0.5mMol) of the free amine from Step 1, 0.075g (0.5mMol) of 3.3-diphenylpropionic acid, O.lg (0.5mMol) of EDCI, 0.08g (0.5mMol) of N-hydroxybenzotriazole in 2mL of dimethylformamide was stirred at 25° for 12h. The mixture was diluted with ethyl acetate and extracted with IN aqueous hydrochlodic acid and saturated aqueous sodium bicarbonate. Drying over magensium sulfate and removal of the volatiles in vacuo. followed by trituration with ether afforded the intermediate dimethylacetal as a white solid (0.2g). Step 3: A solution of O.lg (0.15mMol) of the material obtained in Step 2 in lOmL of tetrahydrofuran and ImL of IN aqueous hydrochloric acid was heated to 70° for 2h. The mixture was diluted with ethylacetate and extracted with saturated aqueous sodium bicarbonate. Drying over magnesium sulfate, removal of the solvent in vacuo and trituration with 10% ethylacetate/ether afforded the desired compound as a pale green solid )0.06g). IH-NMR (DMSO-d 6 ): Step 1: 0.78(12H), 1.02(2H), 1.60(2H), 2.77(1 H), 2.92(2H), 3.21(1H), 3.24(6H), 4.20(3H), 6.95-7.05(3H), 7.35(1H), 7.48(1H), 7.95(2H), 10.78(1H) Step 2: 0.57-0.82(12H), 0.95(1H), 1.15(1H), 1.30(1H), 1.58(2H), 2.75(2H), 2.90(1H), 3.08(1H), 3.27(3H), 3.28(3H), 4.0-4.2(4H), 4.44(1H), 6.9-7.35(14H), 7.43(1H), 7.64(1H), 7.72(1H), 7.95(1H), 10.70(1H) Step 3: 0.5-0.9(12H), 1.00(1H), 1.05(3H), 1.35(1H), 1.60(2H), 2.75(1H), 2.98(1H), 3.15(2H), 4.10(1H), 4.18(1H), 4.42(2H), 6.95-7.95(14H), 7.48(1H), 7.80(1H), 7.85(1H), 8.38(1H), 9.42(1H), 10.85(1H) LRMS (FAB): Step 1 : 461.6 (M+l) Step 2: 670 (M+l) Step 3: 623.7 (M+l) Anal.: Step 1 : C,H,N Step 2: C,H,N Step 3: C,H.N Example 59 N-r3-PhenvlpropionvlVL_isoleucvl-L_isoleucine-L-N-[l-formvl]2-dH-indol-3- yl thyl] amide: Step 1 : A solution of 0.23g (0.5mMol) of the product of Step 1 in Example 58 in 2mL of dimethylformamide and 3mL of pyridine was treated with 0.25mL of 3-phenylpropionyl chloride (Aldrich Chemicals). The mixture was stirred at 25° for 4h and quenched with 2mL of water. After 3h the volatitles were removed in vacuo and the residue was partitioned between ethyl acetate and IN aqueous hydrochloric acid, the organic layer was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulphate and concentrated in vacuo. Trituration with ether afforded the desired dimethylacetal (0.2g) as a white solid. Step 2: O.lg of the product of Step 1 were treated in an analogous manner to Step 3 in Example 58, to afford the desired aldehyde (0.07g) as a white solid. IH-NMR (DMSO-d 6 ): Step 1: 0.75(12H), 1.00(2H), 1.38(2H), 1.65(2H), 2.41(2H), 2.77(3H), 2.90(1H), 3.24(3H), 3 5(3H), 4.18(4H), 6.98(1H), 7-7.2(7H), 7.28(1H), 7.44(1H), 7.73(2H), 7.96(1H), 10.72(1H) Step 2: 0.70(12H), 0.98(2H), 1.38(2H), 1.63(2H), 2.45(2H), 2.65(2H), 2.98(1H), 3.18(1H), 4.20(2H), 4.40(1H), 6.98(1H), 7.02(1H), 7.15-7.22(6H), 7.25(1H), 7.50(1H), 7.78(1H), 7.84(1H), 8.40(1H), 9.44(1H), 10.85(1H) LRMS (FAB): Step 1 : 593.8 (M+l) Step 2: 547.7 (M+l) Anal.: Step l : C,H,N Step 2: C,H,N Example 60 N-acetyl-T,-isoleucvl- -isoleucine-L-N-[l-formvll2-dH-indol-3-v11ethvl]amide Step 1 : A solution of 0.08g (0.18mMol) of the free amine obtained in Step 1 of Example 58 in 0.5mL of pyridine was treated with 0.055g (0.54 mMol) of acetic anhydride. The mixture was stirred at 0° for 3h and the volatiles were removed in vacuo. The residue was partitioned between IN aqueous hydrochloric acid and ethyl acetate and the organic layer was washed with saturated aqueous sodium bicarbonate. Drying over magnesium sulfate and removal of the volatitles in vacuo afforded the desired acetal as a foam (0.14g). Step 2: The crude product from Step 1 was converted to the desired aldehyde (0.07g off-white solid) in an analogous manner to the procedure use for Step 3 in example 58. IH-NMR (CD 3 OD): Step 1: 0.75-0.9(12H), 1.00(2H), 1.31(2H), 1.45(2H), 2.00(3H), 2.88(1H), 3.02(1H), 3.38(3H), 3.42(3H). 4.00(1H), 4.22(2H),6.95-7.1(2H), 7.30(1H), 7.55(1H), 7.82(1H) Step 2: 0.7-l(12H), 1.10(2H), 1.50(2H), 1.75(2H), 1.98(3H), 2.85(1H), 3.08(1H), 4.18(3H), 4.50(1H), 6.98-7.05(5H), 7.25(1H) LRMS (FAB): Step 1 : 503 (M+l) Step 2: 457 (M+l) Anal.: Step l : C,H,N Step 2: C,H,N Example 61 N-r3-Carboxvpropionv1VL-isoleucv1-I_-isoleucine-L-N-fl-formvn2-dH-indo1-3- ylιethyl]amide: A solution of 0.08g (0.18mMol) of the free amine obtained in Step 1 of Example 58 in 0.5mL of pyridine was cooled to 0° and reacted with 0.027g (0.27mMol) of succinic anhydride. The mixture was stirred at 0° for 3h and the volatiles were removed in vacuo. The residue was partitioned between ethyl acetate and IN aqueous hydrochloric acid and the organic layer was washed with water. Drying over magnesium sulfate and removal of the solvent afforded the crude acetal (0.2g) which was used in the next step without purification. Step 2: The material from the first step was converted to the aldehyde in an analogous manner to Step 3 of Example 58 to give the desired product after chromatography on silica gel (6% methanol-dichloromethane) (beige foam). IH-NMR (DMSO-d 6 ): Step 1: 0.82(12H), 1.17(2HO, 1.45(2H), 1.80(2H), 2.58(4H), 2.84(1H), 3.05(1H), 3.37(3H), 3.40(3H, 4.20(3H), 4.38(1H), 7.03(2H), 3.35(1H), 7.55(1H), 7.80(1H) Step 2: 0.65-0.85(12H), 1.10(2H), 1.40(2H), 1.72(2H), 2.40(4H), 3.00(1H), 3.20(1H), 4.20(2H), 4.42(1H), 7.02(2H), 7.18(1H), 7.28(1H), 7.59(1H), 7.80(1H), 7.95(1H), 9.44(lh), 10.88(1H), LRMS (FAB) : Step 1 : 562 (M+l) Step 2: 515.5 (M+l) Anal: Step 2: C,H,N Example 62 N-[5-rhexahvdro-2-oxo-lH-thieno[3.4-dlimidazυl-4-vl]valervl-L-isoleucvl-L- isoleucine-L-N-[l-dimethoxvmethvl12-dH-indol-3-vnethvl1amide: A solution of 0.358g (0.8mMol) of the free amine obtained in Step 1 of Example 58, 0.196g (O.δmMol) of biotin (Aldrich), 0.108g (O.δmMol) of hydroxybenzotriazole, 0.152g (O.δmMol), of EDCI and 0.08g (0.8mMol) of triethylamine in 6mL of dimethylformamide was stirred for 15h at 25°. The mixture was diluted with ethylacetate and water and the resulting precipitate was filtered to give the desired acetal as a white solid (0.47g) IH-NMR (DMSO-d 6 ): 0.78(9H), 1.00-1.80(13H), 2.18(2H), 2.60(2H), 2.7-3.1(), 3.26(), 3.27(3H), 4.1-4.4(4H), 6.4(2H), 6.9-7.1(2H), 7.38(1H), 7.55(1H), 7.75(2H), 7.92(1H), 10.75(1H) LRMS (FAB): 596 (M+l) Anal: C,H,N,S Example 63 N-[5-rhexahvdro-2-oxo-lH-thienor3.4-dlimidazol-4-vl]valervl-L-isoleucvl-I,- isoleucine-L-N-[l-foπτιvl]2-dH-indol-3-vnethv1]amide: 0.4g of the acetal obtained in Example 62 were converted to the aldehyde using a protocol analogous to that used in Step 3 of Example 58 to give the desired compound (0.05 g) as an off-white solid after chromatography on silica gel (5% methanol-dichloromethane). IH-NMR (DMSO-d 6 ) 0.75(12H), 1.00(2H), 1.2-1.7(8H), 2.10(2H), 2.55(1H), 2.6- 3.1(7H), 4.0-4.4(4H), 6.4(2H), 6.9-7.1(2H), 7.35(1H), 7.55(2H), 7.7(1H), 7.85(1H), 9.44(0.5H), 10.65(1H) LRMS: 642 (M+l) Anal: C,H,N,S Example 64 N-[rbenzyloxy.carbonyl]-4-Q-tert-butyl- -aspart-1-vl]-L-isoleucvl-L-isoleucine-L-N- [1 -formyl]2-d H-indol-3-yl ethyl]amide: Step 1: A solution of 0.23g (0.5mMol) of the free amine obtained from Step 3 in Example 58, 0.22g (0.5mMol) of Cbz-(t-bu)Asp-N- hydroxysuccinimide ester (Bachem Bioscienses) and 0.14mL (ImMol) of triethylamine in 5mL of tetrahydrofuran and 5mL of methanol was stirred at 25° for 72h. The mixture was passed through a bed of DOWEX anionexchange resin (OH-form) and washed with methanol. The volatiles were removed in vacuo and the residue was redissolved in methanol. Water was added and the resulting precipitate was filtered and washed with water to give the desired acetal (0.4g) as a white solid. Step 2: A solution of 0.2g (0.28mMol) of the acetal from Step 1 in lOmL of tetrahydrofuran and ImL of IN aqueous hydrochloric acid was heated to 80° for 2h. the mixture was diluted with ethyl acetate and extracted with saturated aqueous sodium bicarbonate. Drying over magnesium sulfate and removal of the solvent in vacuo afforded the desired aldehyde (0.08g) as a white solid IH-NMR (DMSO-d 6 ) : 0.75(12H), 0.97(2H), 1.35(1 IH), 1.65(2H), 2.40(1H), 2.60(1H), 2.95(1H), 3.18(1H), 4.18(2H), 4.38(2H), 5.00(2H), 6.8-8.0(13H), 8.42(1H), 9.42(1H), 10.84(1H) Example 65 N-fben vloxv ' )carbonvπ-L-aspart-ι-vl1-L-isoleucvl-L-isoleucine-L-N-f1-foπnyl]2-d H- indol-3-yπethylJamide: Step 1 : A solution of O.lg (0.13mMol) of the acetal obtained in Step 1 of Example 64 in lOmL of methanol was treated with 0.5g of lithium hydroxide and stirred for lh at 25°. Ethyl acetate was added and the solution was extracted with IN aqueous hydrochloric acid. Drying over magnesium sulfate and removal of the solvent in vacuo afforded the desired acid (O.lg) as a beige solid. Step 2: 0.08g (O.lmMol) of the acid of Step 1 were converted to the aldehyde following an analogous procedure to that used in Step 3 of Example 58 to give the desired compound (0.0 lg) after chromatography on silica gel (5% methanol-dichloromethane). lH-NMR (DMSO-d 6 ) 0.78(12H), 1.05(2H), 1.36(2H), 1.8(2H), 2.6(2H), 2.8(1H), 3.05(1H), 4.0-4.4(4H), 4.99(2H), 6.8-7.6(8H), 7.98(1H), 9.41(1H), 10.82(1H), LRMS: 665 Example 66 N-f[5-('hexahvdro-2-oxo-1H-thieno[3.4-d]imidazol-4-vnvaleramido]hexanov1]]-L- isoleucyl- -isoleucine-I.-N-[l-dimethoxvmethvl]2-dH-indol-3-vnethvl]amide: A solution of 0.07g (O.lόmMol) of the free amine obtained in Step 1 of Example 58, 0.15g (0.33mMol) of biotinamidocaproate n-hydroxysuccinimide ester (Sigma Chemicals), and O.lmL of triethylamine in 5mL of methanol and 5mL of ethyl acetate was stirred at 25° for 12h. The mixture was diluted with ethyl acetate and extracted with IN aqueous hydrochloric acid and saturated aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo to afford the desired acetal (O.lg) as a beige solid. IH-NMR (DMSO-d 6 ): 0.75(12H), 0.9-1.8(16H), 2.05(4H), 2.5-3.1(10H), 3.26(6H), 4.1- 4.4(4H), 6.40(2H), 6.9-7.1(2H), 7.35(1H), 7.52(1H), 7.75(2H), 7.92(1H), 10.73(1H) LRMS (ESMS): 801 (M+l) Anal: C,H,N,S Step 2: O.lg of the acetal obtained in Step 1 was converted to the aldehyde utilizing a procedure similar to that used for Step 3 in Example 58 to give the desired compound as a light brown solid. IH-NMR (DMSO-d 6 ): Step 1: 0.78(12H), 1-1.8(10H), 2.18(2H), 2.79(1H), 2.97(3H), 3.37(3H), 3.39(3H), 4.02(1H), 4.18(3H), 5.02(2H), 6.92-8.0(14H), 10.84(1H). Step 2: 0.78(12H), 1.0-1.8(10H), 2.17(2H), 2.98(3H), 3.20(1H), 4.20(2H), 4.42(1H), 5.00(2H), 6.95-8.0(13H), 8.42(1H), 9.46(1H), 10.88(1H) LRMS: Step 1 : 708 Step 2: 662.5 Anal.: Step 1: C.H.N. Example 67 N-[[5-rhexahvdro-2-oxo-1H-thieno[3.4-dlimidazol-4-vnvaleramidolhexanovlll-L- isoleucvl-L-isoleucine-L-N-[l-formvl12-dH-indol-3-vl-ethvllamide 0.2g of the acetal obtained in Example 66 were converted to the aldehyde using an analogous procedure to that used for Step 3 in Example 58, to give the desired compound (0.098 g) as a white solid. IH-NMR (DMSO-d 6 ) 0.75(12H), 0.9-1.8(15H), 2.10(4H), 2.58(1H), 2.80(1H), 2.9- 3.25(8H), 4.1-4.45(3H), 6.40(2H), 6.9-7.1(2H), 7.18(1H), 7.32(1H), 7.53(1H), 7.70(1H), 7.78(1H), 7.83(1H), 8.40(1H), 9.42(1H), 10.85(1H) LRMS: 755 (M+l) Anal: C,H,N,S Example 68 N-rό-fe-frbenzvloxv ormamidolhexanamidolhexanovπ-L-isoleucyl-L-isoleucine-L-N- [l-dimethoxvmethvI]2-dH-indol-3-yltethyl]arnide: Step 1: A solution of 5.3g (20mMol) of Cbz-6-aminohexanoic acid (Aldrich), 2.3gJ[20mMol) of N- hydroxysuccinimide, 4.8g (25mMol ofEDCI, and 2.8mL (20mMol) of triethylamine in lOOmL of ethylacetate was stirred at 25° for 5h. The mixture was diluted with ehtylacetate and extracted with IN aqueous hydrochloric acid and saturated aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo. The residue was redissolved in 50mL of methanol and treated with 20mL of water, 20mL of ethyl acetate. 2.8mL of triethylamine and 2.6g of 6-aminohexanoic acid. The resulting mixture was stirred for 48h at 25° and then concentrated in vacuo. The residue was diluted with ethyl acetate and extracted with IN aqueous hydrochloric acid and dried over magnesium sulfate. The volatiltes were removed in vacuo and the residue was redissolved in lOOmL of ethyl acetate and 50mL of tetrahydrofuran. 2.3g of N- hydroxysuccinimide and 4.8g ofEDCI were added, followed by 5mL of triethylamine, and the resulting mixture was stirred at 25° for 5h. The reaction was diluted with ethyl acetate and extracted with IN aqueous hydrochloric acid and saturated aqueous sodium bicarbonate, dried over magensium sulfate and concentrated in vacuo. to give the desired activated ester (5.5g) as a white solid. Step 2: A solution of 0.8g (1.73mMol) of the free amine obtained in Step 1 of Example 58, l.Og (2mMol) of the activated ester of Step 1 and 0.28mL (2mMol) of triethylamine in 20mL of methanol was stirred at 25° for lh.0.5g of glycine were added and the mixture was stirred for an additional lh. The volatiles were removed in vacuo and the residue was partitioned between ethyl acetate and IN aqueous hydrochloric acid. The organic layer was extracted with IN aqueous sodium hydroxide and then saturated aqueous ammonium chloride, dried over magnesium sulfate, concentrated in vacuo and triturated with ether to afford the desired acetal (1.2g) as a white solid. IH-NMR (DMSO-d 6 ): Step 1 : 1.2-1.6(12H), 2.00(2H), 2.63(2H), 2.78(4H), 2.97(4H), 5.00(2H), 7.20(1H), 7.38(5H), 7.75(1H), Step 2: 0.75(12H), 1.00(2H), 1.2-1.5(14H), 1.66(2H), 2.00(2H), 2.09(2H), 2.75(1H), 2.95(4H), 3.23(3H), 3.24(3H), 4.18(4H), 4.98(2H), 6.97(1H), 7.00(2H), 7.38(8H), 7.46(1H), 7.65(2H), 7.88(1H), 10.72(1H), LRMS Step 1 : (476.5 (M+l) Step 2: 822 (M+l) Anal: Step 1: C.H.N Step 2: C,H,N Example 69 N-[6-f6-[d .2.3.6-tetrahydro-2.6-dioxo-4-pyrimidinvn formamido] hexanamido] hexanoyl]-L soleucyl-L-isoleucine-L-N-f1 -formvη2-dH-indol-3-vl.ethvllamide Step 1 : A solution of 1 g (1.2mMol) of the compound obtained in Example 68 in 150mL of methanol was treated with O.lg of 5% palladium on carbon and stirred under a hydrogen atmosphere at 25° for 2h. The mixture was filtered through a bed of Celite and the volatiles were removed in vacuo. The residue was triturated with ether to give the free amine (0.85g) as a white powder. Step 2: A solution of 0.137g (0.2mMol) of the free amine of Step 1, 0.052g (0.3mMol) of orotic acid (Aldrich), 0.058g (0.3mMol) ofEDCI, 0.044g (0.3mMol) of N- hydroxybenzotriazole in ImL of dimethylformamide was stirred at 25° for 12h. The volatiles were removed in vacuo and the residue was partitioned between ethylacetate and IN aqueous hydrochloric acid. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo to give the crude acetal as a foam. Step 3: The acetal obtained in Step 2 was converted to the desired aldehyde utilising a similar procedure to that described for Step 3 in Example 58. The aldehyde was obtained as an off-white solid (0.08g). IH-NMR (DMSO-d 6 ) Step 1 : 0.78(12H), 1.10(2H), 1.2-1.6(14H), 1.68(2H), 2.03(2H), 2.12(2H), 2.85(1H), 2.8-3.05(5H), 3.36(3H), 3.38(3H), 4.18(4H), 7.95-7.05(3H), 7.30(1H), 7.48(1H), 7.65(2H), 7.94(1H), 10.72(1H), Step 2: (CD3OD) 0.7-0.9(12H), 1.15(2H), 1.2-1.8(16H), 2.18(2H), 2.24(2H), 2.8- 3.2(4H), 3.3(2H, 3.38(3H), 3.39(3H), 4.19(1H), 4.20(2H), 4.38(1H), 6.08(1H), 6.95- 7.1(3H), 7.30(1H), 7.57(1H), Step 3: 0.78(12H), 1.05(2H), 1.2-1.8(16H), 2.05(2H), 2.17(2H), 2.95-3.2(6H), 4.20(2H), 4.42(1H), 5.99(1H), 6.98(1H), 7.05(1H), 7.18(1H), 7.35(1H), 7.50(1H), 7.70(1H), 7.77(1H), 7.83(1H), 8.42(1H), 8.78(1H), 9.44(1H), 10.68(1H), 10.85(1H), 11.27(1H) LRMS: Step 1 : 688 Step 2: 826 Step 3: 780 Example 70 N-[6-[6-2-f2.5-dioxo-4-imidazolidinvl>acetamidol1 hexanamido1hexanovl]-L-isoleucv1- L-isoleucine-L-N-[1 -formyll2-dH-indol-3-yl .ethvnamide: Step 1: 0.047g of hydantoinacetic acid was coupled to the free amine obtained in Step 1 of Example 69 according to the procedure used for Step 2 in example 69 to afford 0.025g of the desired product as a beige solid. Step 2: The acetal obtained in Step 1 was converted to the aldehyde (0.0 lg) using a protocol similar to the one utilised in Step 3 of Example 69 1HNMR (CD 3 OD): Step 1 : 0.78-0.95(12H), 1.10(2H), 1.2-1.6(14H), 1.78(2H), 2.17(2H), 2.22(2H), 2.59(1H), 2.72(!H), 2.84(1H), 3.03(1H), 3.15(4H), 3.38(3H), 3.40(3H), 4.18(3H), 4.37(2H), 7.00(3H), 7.34(1H), 7.58(1H), Step 2: 0.7-0.9(12H), 1.15(2H), 1.2-1.8(16H), 2.I8(2H), 2.23(2H), 2.5-3.1(8H), 4.20(2H), 4.37(1H), 4.50(1H), 6.9-7.1(3H), 7.27(1H), 7.58(1H), LRMS Step 1 : 828 Step 2: 782 Anal: Step 2: C,H,N Example 71 N-[6-rben7vloxv^carhonvlaminohexanovl1-L-isoleucvl-L-isoleucine-L-N l-formvπ2- d H-indo]-3-vDethyl]amide Step 1 : Cbz-6-aminohexanoic acid was coupled to the free amine (0.4g) obtained in Step 1 of Example 58 using a protocol analogous to that used in Step 2 of Example 58 to give the desired acetal as a white solid. Step 2: O.lg of the acetal obtained in Step 1 was converted to the aldehyde utilising a procedure similar to that used for Step 3 in Example 58 to give the desired compound as a light brown solid. IH-NMR (DMSO-d 6 ): Step 1 : 0.78(12H), 1-1.8(10H), 2.18(2H), 2.79(1H), 2.97(3H), 3.37(3H), 3.39(3H), 4.02(1H), 4.18(3H), 5.02(2H), 6.92-8.0(14H), 10.84(1H), Step 2: 0.78(12H), 1.0-1.8(10H), 2.17(2H), 2.98(3H), 3.20(1H), 4.20(2H), 4.42(1H), 5.00(2H), 6.95-8.0(13H), 8.42(1H), 9.46(1H), 10.88(1H), LRMS: Step 1 : 708 Step 2: 662.5 Anal: Step 1 : C,H,N Step 2: C,H,N Example 72 N-Pentanovl-L-isoleucvl-L-isoleueine-L-N-f 1 -formvl 2-f 1 H-indol-3-vnethv1]amide Step 1 : A solution of 0.4g (0.86mMoI), of the free amine obtained in Step 1 of Example 58 in 5mL of pyridine was treated with 0.02g of 4-dimethylaminopyridine and 0.13g (1.08mMol) of pentanoylchloride at 0°. The mixture was stirred at 25° for 12h and the volatiles were removed in vacuo. The residue was partitioned between ethyl acetate and IN aqueous hydrochloric acid. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo to give the desired acetal (0.36g) as a white solid. Step 2: O.lg of the acetal from Step 1 were converted to the aldehyde (0.05g white solid) utilising a protocol analogous to that used in Step 3 of Example 58. IH-NMR (DMSO-d 6 ) Step 1 1:0.6-0.85(15H), 1.0-1.8(10H), 2.17(2H), 2.80(1H), 2.95(1H), 3.36(3H), 4.20(4H), 6.95-8.00((7H, 10.75(1H), Step 2: 0.65-.086(15H), 1.00-1.80(10H), 2.19(2H), 3.22(1H), 3.40(1H), 4.20(2H), 4.41(1H), 6.95-8.00(7H), 9.54(1H), 10.72(1H), LRMS Step 1: 545 Step 2: 499.5 Anal.: Step 1: C,H,N Step 2: C,H,N Example 73 N-[r3-methoxycarhonvnpropionv -L-i.so;eucvl- -isoleucine-L-N-[1- dimethoxymethv1]2-dH-indo1-3-vnethvllamide 3-N-methoxycarbonylpropionylchloride was coupled to 0.4g of the free amine obtained in Step 2 of Example 58 using an analogous procedure to that outlined for Step 1 in Example 72 to give the dimethylacetal (0.39g) as a white solid. IH-NMR (DMSO-d 6 ) 0.78(12H), 1.05(2H), 1.38(2H), 1.90(2H), 2.44(4H), 2.78(1H), 2.96(1H), 3.37(6H), 3.58(3H), 4.18(4H), 6.60(1H), 7.00(3H), 7.38(1H), 7.55(1H), 7.75(2H), 8.00(1H), 10.73(1H), LRMS: 575 Anal.: C,H,N Example 74 N-[r3-methoxvcarbonv1.propionvη-L-isoleucvl-L-isoleucine-L-N 1-foττnvη2-dH- indol-3-yDethyl]amide O.lg of the acetal from Example 73 were converted to the aldehyde (0.05g white solid) utilising a protocol analogous to that used in Step 3 of Example 58. IH-NMR (DMSO-d 6 ): 0.78(12H), 1.05(2H), 1.40(2H), 1.72(2H), 2.42(4H), 3.00(1H), 3.20(1H), 3.58(3H), 4.20(2H), 4.42(1H), 7.01(2H), 7.18(1H), 7.38(1H), 7.56(1H), 7.80(1H), 8.42(1H), 9.44(1H), 10.88(1H), LRMS: 529 Anal.: C,H,N Example 75 N-[benzvloxvcarbonvll-L-trvptophanvl-L-trvptophan-L-N-fl -semicarbazonomethv1]2- dH-indol-3-yπethyl]amide: Step 1 : Boc-Tryptophan (60g) was coupled with N,O- dimethylhydroxylamine using a protocol similar to that used for Step 2 of Example 58 to give Boc-Tryptophan-N,O-dimethylhydroxamide (52g) as a white solid. Step 2: 40g of the amide of Step 1 were converted to the aldehyde using a procedure analogous to that used in Example 15 to give 30g of Boc-Tryptophanal as a white solid. Step 3: 7.0g of Boc-Tryptophanal were converted to the semicarbazone (5.0g, white solid) using a protocol analogous to that utilised in Example 56. Step 4: 2.5g (7.2mMol) of the semicarbazone obtained in Step 3 were dissolved in 25mL of dichloromethanbe and treated for 3h with 24mL of trifluoroacetic acid. The volatiles were removed in vacuo and the residue was coupled to Cbz-TrpTrp (Bachem Biosciences) using a protocol similar to that utilised in Step 2 of Example 58 to give the desired semicarbazone (1.5g, white solid) after chromatography on silica gel (10% methanol/dichloromethane) . lH-NMR(DMSO-d 6 ) Step 3:1.4((9H), 2.98(2H), 4.38(1H), 6.30(1H), 7-7.6(7H), 9.85(1H). 10.8(1H), Step 4: (CDCI3): 3.2(6H), 4.8(3H), 5.00(2H), 6.9-7.8(20H) LRMS: Step 4: 604 (M+Na) Anal: CH.N Example 76 N-trbenzvloxvtcarbonvlj-L-aspart-l-vlj- -isoleucvl-L-isoleucine-L-N-fl- dimethoxymethv1]2-dH-indo1-3-vnethvl]amide A solution of O.lg (0.13mMol) of the acetal obtained in Step 1 of Example 64 in lOmL of methanol was treated with 0.5g of lithium hydroxide and stirred for lh at 25°. Ethyl acetate was added and the solution was extracted with IN aqueous hydrochloric acid. Drying over magnesium sulfate and removal of the solvent in vacuo afforded the desired acid (O.lg) as a beige solid. lH-NMR(MeOH-d 4 ) 0.8(12H), 1.15(2H), 1.50(2H), 1.85(2H), 2.95(2H), 3.05(1H), 3.45(3H), 3.50(3H), 4.25(3H), 4.42(1H), 4.62(1H), 5.20(2H), 7.0-7.2(3H), 7.4(5H), 7.6(1H) LRMS: 711 Example 77 N-Benzyloxycarbonyl-R-isoleucyl-S-isoleucine-1-S-formvl-2-dH-indol-3-v1V ethylamide The title compound was obtained in an analogous manner to the procedure outlined for Example 15, utilising a D-amino acid instead of an L-amino acid in the appropriate step of the sequence. IH NMR (DMSO) δ: 0.63-0.93 (12H), 0.98-1.8 (4H), 2.62-3.07 (2H), 3.84-4.51 (3H), 5.06 (2H), 6.17-6.21 (IH), 6.31-6.36 (IH), 6.93-7.83 (10H), 8.48-8.52 (IH), 9.47 (IH), 10.63-10.84 (IH) LRMS: (El, m/e): 549 (M + +l) Anal. (1 H 2 O): C: 65.96, H: 7.60, N: 10.10 Example 78 N-[[5-rhexahvdro-2-oxo-lH-thienof3.4-dlimidazol-4-vnvaleramidolhexanov1]]- - trvptophanvl- -trvptophan- -N-fl-dimethoxvmethvll2-dH-indol-3-v1.ethvl]amide 0.37g of the dimethylacetal of TrpTrpTrp aldehyde, obtained using procedures similar to those utilised for the synthesis of the llelleTrp analog described in Step 1 of Example 58 was biotinylated using the protocol outlined for Example 66 to give the desired product (0.4g) as a white solid. IH-NMR (DMSO-d 6 ): 1.0-1.8(12H), 1.95(2H), 2.58(1H), 2.7-3.1(13H), 3.37(3H), 3.39(3.H), 4.12(2H), 4.25(1H), 4.5(1H), 6.4(2H), 6.96-8.00(19H), 10.75(2H), 10.80(1H), LRMS: 946 (M+l) Anal: C,H,N,S Example 79 N-[12-[rbenzyloxy.acetamidoldodecanovl]-L-isoleucvl-L-isoleucine-L-N-fl-formvll2- dH-indol-3-vπethyl]amide 0. lg of the desired compound was obtained from the free amine prepared in Step 1 of Example 58 and 12-Cbz-amidododecanoic acid using the squence utilised for Steps 2 and 3 of Example 58. IH-NMR (CDCI 3 ) 0.8(12H)), 1.0-2.0(24H), 2.20(2H), 3.18(4H), 4.37(2H), 4.80(2H), 5.08(2H), 5.08(2H), 7.0-7.6 (1 IH), 8.40(1K), 9.58(1H), LRMS: 796 (M+2MeOH) Anal: C.H,N Example 80 N-Benzvloxvcarhonvl- -i.soleucvl-L-isoleucine-L-Nrn racetoxvacetamido]2-dH-indol- 3-yl .ethyl]amide Step 1 : Isobutylchloroformate (4.49g, 36.2mmol) was added dropwise to a stirring solution of Boc-(D or L)-Trp-OH (lO.OOg, 32.9mmol) in THF (120ml) cooled to -10°C. The resulting white reaction mixture was stirred 15 min and filtered into a round bottom flask equipped with a stir bar. The stirring filtrate was cooled to - 10°C and TMSN3 (6.6ml, ca 49.4mmol) was added dropwise and the solution stirred an additional 1.5h at -10°C. The solution was concentrated at room temperature and the oil dissolved in EtOAc (150ml). The EtOAc solution was washed with sat. NaHCO3 (2 x 30ml) and brine (2x 30ml), dried over MgSO4, filtered and concentrated. The crude material was dissolved in toluene (200ml) and the solution heated to 40°C and maintained for lh. DABCO (0.52g, 4.62mmol) was added and the solution maintained at 40°C for an additional 18h. Concentration in vacuo and flash chromatography (silica gel;) 30% EtOAc/Hesanes) followed by crystallisation from Et2θ provided the title compound 1 (6.20g, 15.1mmol, 46% yield) as a white solid. Step 2: A solution of the product of Step 1 (2.02g, 4.93mmol) in a mixture of MeOH (60ml) and THF (10ml) was hydrogenolyzed over Pd/C at 20 psi for 3h. The mixture was filtered and concentrated to provide the free amine as an oil which was used immediately in the next step. A stirring solution of the free amine (4.93mmol) in DMF (25ml) was cooled in an ice bath and Z-lle-lle-OH (1.87g, 4.93mmol), EDCI (0.954g, 4.93mmol) and HOBT (0.666gm 4.93mmol) were added and the mixture stirred 3h with gradual warming to room temperature. The deep red solution was concentrated in vacuo and the crude partitioned between EtOAc (75ml) and 5% citric acid (25ml). The layers were separated and the organic layer washed with sat. NaHCO3 (2 x 25ml) and brine (1 x 25ml), dried over MgSO4 filtered and concentrated. The crude material was purified by flash chromatography (silica gel; 50% EtOAc/Hexane) which provided the desired tripeptide (1.41g, 2.05mmol, 42% yield) as an off white solid; 50:50 mixture of diastereomers. Step 3: A stirring mixture of the product obtained in Step 2 (21 lmg, 0.332mmol) in THF (1.1ml) was cooled in an ice bath under N 2 atmosphere. Neat TFA (2ml) was added slowly dropwise. The dark reaction mixture was stirred 1.5h. The mixture was concentrated cold at reduced pressure and triturated with Et2θ. The resulting solid material (0.446mmol), NMM (0.669mmol), and acetoxy acetic acid (0.446mmol) were dissolved in DMF (5ml) and the solution cooled in an ice bath. EDCI (0.446mmol) was added via spatula and the reaction mixture stirred for 3h with warming to room temperature. The mixture was concentrated and the crude oil partitioned between EtOAc (10ml) and 5% citric acid (5ml). The layers were separated and the EtOAc layer washed with sat. NaHCO3 (5ml) and brine (5ml), dried over MgSO4, filtered and concentrated, flash chromatography on silica gel (EtOAc/Hexane eluent) provided the title compound as a tan solid; 57.43 mixture of diastereomers; Step l: mp 132-133°C; lH NMR (DMSO-d 6 ) 10.81 (IH), 7.59 (2H), 7.33 (6H), 7.16 (IH), 7.06 (3H), 5.22 (IH), 5.01 (2H), 2.99 (2H), 1.36 (9H); FAB-MS: 410 (M+l) Step 2: IH NMR (DMSO-d 6 ) 10.78 (IH), 8.13 (IH), 7.80 (IH), 7.60 (IH), 7.34 (7H), 7.05 (4H), 5.40 (IH), 5.05 (2H), 4.4-3.9 (2H), 2.95 (2H), 1.73 (2H), 1.6-0.9 (4H) 1.33 (9H), 0.8 (12H); FAB MS 636 (M+l). Step 3: IH NMR (DMSO-d 6 ) 10.81 (IH), 8.24 (2H), 7.82 (IH), 7.60 (IH), 7.34 (7H), 7.15-6.90 (3H), 5.61 (IH), 5.04 (2H), 4.44, 4.38, 4.4-3.9 (2H), 3.04 (2H), 2.08, 2.05), 1.69 (2H) 1.42 (2H), 1.11 (2H), 0.80 (12H); FAB MS: 636 (M+l) Example 81 N-r3-pyri(iv1methoxy')carhonyl-L-isoleucvl-L-isoleucine-L-N-f1 -formvl]2-dH-indol-3- yl .ethyljamide Step 1 : A solution of Cbz-lle-lle-Trp-N(Me)OMe obtained according to the procedures outlined in Examples 1-14, in THF (8ml) and MeOH (20ml) was hydrogenolyzed over 10% Pd-C (O.lg) at 40 psi for 2h. The mixture was filtered and concentrated to provide the free amine as a white solid. Step 2: A solution of 3-pyridylcarbinol (0.207g, 1.90mmol) and triethyl amine (0.689g, 6.81 mmol) in Et2θ (5ml) was cooled in an ice bath and a solution of triphosgene (0.189g, 0.637mmol) in Et2θ (2ml) was added dropwise. The resulting mixture was stirred for 30 min at 0°C. A solution of the free .amine of Step 1 (0.200g, 0.422mmol) in THF (2ml) wad added and the reaction mixture was allowed to warm to room temperature and stirred for 18h. The reaction mixture was concentrated by rotovap and diluted with EtOAc. The EtOAc mixture was washed with brine, dried over MgSO4 filtered and concentrated. Flash chromatography on silica gel eluting with 5% MeOH/CH2Cl2 provided the desired amide as an off white solid, 93mg (0.153mmol) of which was dissolved in THF (3ml), was cooled to -60°C and LAH (lOOmg, 2.64mmol) was added slowly via spatula. The reaction mixture was stirred at -60°C for 1.5h, warmed to 0°C and quenched with 10% ctiric acid, the mixture was basified to pH 10 with IN NaOH and the THF was removed by rotovap. The aqueous mixture was extracted with EtOAc and the combined EtOAc layers were washed with H2O and brine, dried over MgSO4, filtered and concentrated, the resulting material was recrystallised from EtOAc/Hexane to provide the title compound as a white solid. Step 1 : FAB-MS: 474 (M+l) Anal.: C,H,N Step 2: FAB-MS: 550 (M+l) Anal.: C,H,N Example 82 N-rbenzyloxy^carbonvl-L-isoleucvl-L-isoleucine-L-N-ri-rrf -rethoxvcarbonvlV2- oxiranyl]carbonyl]amidolmethv1]-2-dH-indol-3-vnethvllamide Step 1: A solution of 2g (5.6mMol) of the mesylate obtained in Step 1 of Example 57 and 5g of lithium azide in 25mL of dimethylformide was heated to 100° for 3h. The volatiles were removed in vacuo and the residue was partitioned between dichloromethane and water. The organic layer was dried over magnesium sulfate, concentrated in vacuo and chromatographed on silica gel (25%-40% ethylacetate/hexanes) to give the desired azide (0.8g) as a white solid. Step 2: 0.5g (l.όmMol) of the azide from Step 1 were dissolved in 15mL of dichloromethane and treated with lOmL of trifluoroacetic acid. The resulting mixture was stirred at 25° for 0.5h and the volatiles were removed in vacuo. The residue was partitioned between dichloromethane and IN aqueous sodium hydroxide. The organic layer was dried over magnesium sulfate and concentrated in vacuo, redissolved in 5mL of dimethylformamide and treated with 1.32g (3mMol) of BOP and 0.945g (2.5mMol) of Cbz-llelle (Bachem Bioscience), followed by 0.3g (3mMol) of N-methylmorpholine. The resulting mixture was stirred at 0° for 24h. diluted with ethylacetate and extracted with IN aqueous hydrochloric acid and saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, concentrated in vacuo and chromatographed on silica gel (50% ethylacetate/hexane) to give the tripeptide azide (0.8g) as a white solid. Step 3: A solution of 3.0g (5.2mmol) of the azide from Step 2 and 1.8g (6.9mmol) of PI13P in a solvent mixture of H2O (1.6mL), THF (30mL) and CH3CN (30mL) was stirred at room temperature overnight. The solution was evaporated in vacuo to dryness. The residue was chromatographed on a short silica gel pad eluted with EtOAc:hexane/l:l followed by CH2Cl2:MeOH/9:l to give 1.95g of the desired amine as a white solid. Step 4: To a solution of 0.2g (0.36mmol) of the amine obtained in Step 3 and 0.1 lg (0.39mmol) of trans-3-ethoxycarbonyloxiranylpropionic acid p-nitrophenylester in CHCI3 (lOmL) was added 0.04g (0.4mmol) of triethylamine. After stirring at room temperature for 40 min, the reaction went to completion as determined by TLC. The resulting precipitate was filtered to give 0.106 solid of the desired product. The filtrate was washed with 0.1 N NaOH. 0.1 N HCl and H2O, dried over MgSO4 and evaporated in vacuo to give another 0.052g of the desired compound as a solid (as a mixture of two diastereomers). 1H NMR Step 1: (CDCI3) 0.41 (9H). 2.28 (2H), 3.38 (2H), 4.05 (IH), 4.7 (IH), 7.03 (IH), 7.1-7.3 (2H), 7.38 (IH), 7.64 (IH), 8.18 (IH), Step 2: (CDCI 3 ) 0.80 (12H), 1.11 (2H), 1.42 (2H), 1.85 (2H), 2.98 (2H), 3.38 (2H), 4.00 (IH), 4.20 (IH), 4.49 (IH), 4.98 (IH), 5.10 (2H), 5.3 (IH), 6.20 (IH), 6.40 (IH), 7-7.4 (10H), 7.60 (IH), 8.20 (IH), Step 4: 0.6-0.9 (12H), 1.1 (3H), 1.21 (3H), 1.4 (IH), 1.7 (2H), 2.80 (2H), 3.3 (2H), 3.55 (IH), 3.61 (IH), 3.95 (IH), 4.1 (3H), 4.3 (IH), 5.00 (2H), 6.95 (IH), 7.05 (IH), 7.15 (IH), 7.30 (6H), 7.45 (IH), 7.55 (IH), 7.70 (IH), 7.85 (IH), 8.30 (IH), 10.80 (IH). LRMS Step 1 : 315, Step 2: 577, Step 4: 692 Anal. Step 1 : C,H,N Step 2: C,H,N Step 3: C,H,N Step 4: C,H,N Example 83 N-(benzvloxv.carhonv1-L-isoleucvl-L-isoleucine-L-N-[1 -[r3- maleimidopropionamido]methvl]-2-dH-indo1-3-vl .ethv1]amide A solution of O.lg (O.lδmmol) of the amine obained in Step 3 of Example 82 and 0.75g (0.28mmol) of 3- maleiimidopropionic acid hydroxysuccinimideester in CH2CI2 (5mL) was stirred at room temperature. To this solution was added 0.02g (0.2mmol) of triethylamine. After stirring for 2h, the resulting precipitate was filtered to give 0.057g of the desired compound as a solid. IH NMR (DMSO-d 6 ) δ 0.6-0.8 (12H), 0.95 (IH), 1.15 (2H), 1.4 (IH), 1.70 (2H), 2.35 (2H), 2.75 (2H), 3.1 (IH), 3.2 (IH), 3.60 (2H), 4.00 (2H), 4.05 (IH), 4.25 (IH), 5.02 (2H), 6.95 (IH), 6.96 (2H), 7.00 (IH), 7.05 (IH), 7.31 (6H), 7.40 (IH), 7.55 (IH), 7.65 (IH), 7.85 (IH), 7.90 (IH). LRMS: (FAB) m/e 701 (M+l) Anal: CHN Example 84 N-fbenzyloxy.carbonvl-L-isoleucvl-T.-isoleucine-L-N-|ϊ2- maleimidoacetamido]methvl]-2-dH-indo1-3-vl.ethv1.amide A solution of 0.2g (0.36mmol) of the amine obtained in Step 3 of Example 82, 0.06g (0.40mmol) of maleimidoacetic acid (J. Med. Chem. 1975, 18, 1004), 0.08g (0.79mmol) of N- methylmorpholine, 0.056g (0.41 mmol) of hydroxybenzotriazole and 0.076g (0.40mmol) ofEDCI in DMF (5mL) was stirred at room temperature overnight. The solution was evaporated in vacuo. The residue was partitioned between EtOAc and saturated aqueous NaHCO3- The separated EtOAc solution was washed with 1 N HCl and then H2O, dried over MgSO4 and evaporated in vacuo to dryness. Recrystallisation of the residue from THF/Et2θ gave 0.13g of the title compound. 1H NMR (DMSO-d 6 ) δ 0.65-0.85 (12h), 1.1 (2H), 1.4 (2H), 1.7 (2H), 2.75 (2H), 3.05- 3.20 (2H), 3.9-4.2 (5H), 5.03 (2H), 6.95 (IH), 7.08 (IH), 7.09 (2H), 7.25-7.35 (7H), 7.55 (IH), 7.8 (2H), 8.1 (IH). LRMS: (FAB) m/e 687 (M+l) Anal: C,H,N Example 85 N-rben7v1oxv.carbonv1-L-isoleucvl-L-isoleucine-L-N-[l-[r2-chloroacetamido]methv1]- 2-( 1 H-indol-3-yπethyl]amide A solution of 0.15g (0.26mmol) of the free amine obtained in Step 3 of Example 82, 0.2g (1.8)mmol) chloroacetyl chloride and 0.3g (2.2mmol) of potassium carbonate in CHCI3 (5mL) was stirred at room temperature for lh. After filtration of the insoluble material, the CHCI3 solution was evaporated in vacuo to dryness. The residue was stirred in Et2θ and filtered to give 0.087g of the title compound. 1H NMR (DMSO-d 6 ) δ 0.6-0.8 (12H), 1.15 (IH), 1.4 (IH), 1.70 (IH), 2.80 (2H), 3.20 (2H), 3.9 (IH), 4.03 (2H), 4.1 (IH), 4.3 (IH), 5.02 (2H), 6.9 (IH), 7.05 (IH), 7.15 (IH), 7.31 (6H), 7.4 (IH), 7.55 (IH), 7.8 (2H), 8.1 (IH). LRMS: (FAB) m/e 626 (M+l) Anal: CHNCI Example 86 N-rbenzyloxy.carbonv1-L-isoleucvl-L-isoleucine-L-N-fl-[r2- hvdroxyacetamidolmethv1]-2-dH-indol-3-vnethvll amide Step 1: A mixture of 0.55g (lmmol) of the free amine obtained in Step 3 of Example 82, 1.5g (1 lmmol) of acetoxyacetyl chloride and 2g (15mmol) of potassium carbonate in CHCI3 (60mL) was stirred at room temperature for 1 l/2h. H2θ(20mL) was added . The CHCI3 solution was separated dried over MgSO4 and evaporated in vacuo to dryness. The residue was chromatographed on silica gel with CHCI3 followed by 5% MeOH in CHCI3 to give 0.22g of the desired acetoxy compound. Step 2: To a solution of 0.033g (O.όmmol) of NaOMe in MeOH (5mL) was added 0.4g (O.όmmol) of the acetoxy compound obtained in Step 1. After stirring at room temperature for lh, the solution was neutralised with IN HCl. The mixture was evaporated to almost dryness and the residue was partitioned between EtOAc and H2O. The EtOAc solution was dried over MgSO4 and evaporated in vacuo to give 0.2g of the tile compound.. IH NMR (DMSO-d 6 ) Step 1: IH NMR (DMSO-d 6 ) δ 0.6-0.8 (12H), 1.1 (2H), 1.1 (2H), 1.4 (2H), 1.7 (2H), 2.50 (3H), 2.75 (2H), 3.15 (2H), 3.95 (IH), 4.1 (IH), 4.25 (IH), 4.40 (2H), 5.00 (2H), 6.95 (IH), 7.15 (IH), 7.33 (6H), 7.55-7.95 (5H). Step 2: 0.63-0.85 (12H), 1.1 (2H), 1.4 (2H), 1.7 (2H), 2.8 (2H), 3.15 (2H), 3.75 (2H), 4.0 (IH), 4.1 (IH), 4.3 (IH), 5.0 (2H), 5.45 (IH), 6.95 (IH), 7.05 (IH), 7.15 (IH), 7.33 (6H), 7.45-8.00 (5H). LRMS: Step 1 : 650 (M+l) Step 2: 608 (M+l) Anal. Step 1 : C,H,N Step 2: C,H,NCHN Example 87 N-f 5-hexahvdro-2-oxo-1Η-t)ιieno[3.4-d]imidazol-4-vnvaleramido1hexanov1]]-L- trvptophanvl- -trvptophan-L-N-[1-semicarhazonomethvl]2-riH-indol-3-vnethyl]amide: The product of Step 4 of Example75 was converted to the free amine using a protocol analogous to that used in Step 1 of Example 58 and then coupled to the N- hydroxysuccinimid ester of biotinylamidocaproic acid using a procedure similar to that used in Example 66 to give the desired product as a white solid (0.22g) IH-NMR (DMSO-d 6 ): 1.0-1.6 (14H), 2.03 (4H), 2.7-3.2 (13H), 4.06 (IH), 4.30 (IH), 4.60 (2H), 6.40 (2H), 6.8-8.2 (20H), 9.90 (IH), 10.80 (3H), LRMS: 974.5 (M+NH4) Anal: C,H,N,S Example 88 N-Benzv1oxycarhonv1-L-isoleucvl-I,-isoleucine-L-N-[l-oxalvl12-(phenvnethv1]amide A solution of 0.3g (0.52mMol) of the ethylester obtained in Example 53 in 3mL of methanol was treated with 0.65 mL of IN aqueous sodium hydroxide. The resulting suspension was stirred for 3h at 25° and the now clear solution was diluted with ehtyl acetate. Extraction with IN aqueous hydrochloric acid and saturated aqueous ammonium chloride, followed by drying and removal of the solvent in vacuo, afforded a gum which was triturated with ether to give the desired acid (0.2g) as a white solid. IH-NMR (DMSO-d 6 ): 0.55-0.9(12H), 1.050, 1.38(2H), 1.67(2H), 2.78(1H), 3.06(1H), 3.88(1H), 4.221H), 4.85(1H), 5.00(2H), 7.05-7.4(1 IH), 7.63(1H), 8.55(1H) LRMS: 555 (M+l) Anal: C,H,N Example 89 N-(5-phenylpentanoylV -isoleucvl-L-isoleucine-L-N-[l -formvl]2-d H-indol-3- yπethyl]amide This compound was obtained following procedures utilised for Example 59 and starting with commercially available (Aldrich) 5-phenylpentanoic acid. IH-NMR (DMSO-d6): 0.88(12H), 1.3-1.9(12H), 2.18(2H), 3.00(1H), 3.20(1H), 4.20(2H), 4.40(1H), 6.98-7.98(13H), 9.48(1H), 10.88(1H) LRMS: 575.5 (M+H) Anal: C,H,N Example 90 N-r3-phenoxvpropionvni-T.-isoleucvl-L-isoleucine-L-N-[l-formvn2-dH-indol-3- ylfethyljamide This compound was obtained following the procedures utilised for Example 59 and starting with commercially available (Aldrich) 3-Phenoxypropanoic acid. lH-NMR(DMSO-d 6 ): 0.84(12H), 1.04(2H), 1.40(2H), 1.70(2H), 2.60(2H), 3.00(1H), 3.20(1H), 4.1-4.4(5H), 6.8-7.4(9H), 7.55(1H), 7.84(1H), 8.04(1H), 8.44(1H), 9.50(1H), 10.88(1H) LRMS: 563.5 (M+H) Anal: C,H,N Example 91 N-r5-rhexahvdro-2-oxo-1H-thieno[3.4-d]imidazol-4-vl.pentanovl]-L-trvptophanvl-I,- trvptophan-L-N-[1 -formvl]2-d H-indol- -vl .ethvl]amide A solution of 0.9g (0.77mMol) of Cbz-Trp Tip Trp-N,O-dimethylhydroxamide obtained according to the general procedures outlined above, in 150mL of methanol was treated with O.lg of 5% palladium on Charcoal and stirred under an atmosphere of hydrogen gas for 4h. The mixture was filtered through a bed of Celite and the volatiles were removed in vacuo to give 0.45g of a colorless oil, which was redissolved in 5mL of pyridine and treated with 0.33g (0.89mMol) of biotin-p-nitrophenylester and 0.05g of dimethylaminopyridine. The resulting mixture was stirred for 12h and the volatiles were removed in vacuo. The residue was partitioned between ethyl acetate and IN aqueous hydrochloric acid, the organic layer was washed with aqueous sodium bicarbonate, dried and concentrated in vacuo to give 0.37g of the desired amide as a yellow solid). 2g (0.26mMol) of this material was dissolved in lOmL of tetrahydrofuran and cooled to -78°. The resulting mixture was treated with 0.5mL of IN lithium aluminum hydride in tetrahydrofuran and stirred at -40° for 12h. Quenching the reaction with lOOmL of IN aqueous sodium bisulfate, followed by extraction with ethyl acetate and washing of the organic layer with saturated aqueous sodium bicarbonate afforded the crude aldehyde after concentration in vacuo. Purification on silica gel (5% methanoldichloromethane) afforded 0.08g of the desired product as a pale yellow solid. LRMS: 787 Anal: C,H,N,S Example 92 N-[5-rhexahvdro-2-oxo-1H-thieno[3.4-d]imidazol-4-vnpentanovll-L-p- bromophenvlalanvl-L-1 -naphthvlalanvl-L-N-ri -dimethoxvmethv112-d H-indol-3- ynethyl] amide A solution of p-bromophenylalanyl-1-naphthylalanine lg (2.3mMol), obtained according to the general procedures outlined above, and 1.2g (l lJmMol) of potassium carbonate in 20mL of water was cooled to 0° and treated dropwise with a solution of N-hydroxysuccinimido biotin in lOmL of 1,4-dioxane. The resulting mixture was stirred at 25° for 12h and then acidified to pH2 with IN aqueous hydrochloric acid. The precipitate was collected and washed with water. Drying in vacuo afforded the desired acid as a white solid (1.05g). 0.25g (0.37mMol) of this intermediate were dissolved in 25mL of dimethylformamide and treated with 0.09g (0.37mMol)of tryptophandimethylacetal, 0.07g (0.37mMol) of EDCI and 0.05g (0.37mMol) of N-hydroxybenzotriazole. The mixture was stirred at 25° for 12h and concentrated in vacuo. The residue was partitioned between ethylacetate and IN aqueous hydrochloric acid and the organic layer was washed with saturated aqueous sodium bicarbonate, dried and concentrated in vacuo. Chromatography on silica gel (8% methanol-dichloromethane) afforded the desired acetal as a white solid. LRMS: 884 Anal: C,H,N,S Example 93 N-[5frhexahvdro-2-oxo-1 H-thienor3.4-dlimidazo1-4-vnpentanov -L-p- bromophenvlalanvl-I -1 -naphthvlalanvl-L-N-H -formvl 2-d H-indol-3-vl .ethvljamide lg of the acetal obtained in Example 92 were converted to the aldehyde (0.01 g white solid) according to the procedure outlined for Step 3 in Example 58 LRMS: 837/839 Example 94 N-rbenzvloxv.carhonv1- -p-hromophen^alaπvl-I.-1 -naphthvlalanvl- -N-[l-[2- oxiranylcarbonyl]]2-phenylethy1]amide Step 1: A solution of 1 lg of Boc- phenylalanine-N,O-dimethylhydroxamide in 250mL of tetrahydrofuran was treated with 250mL of IN vinylmagnesium bromide in tetrahydrofuran and the resulting mixture was stirred at 25° for lh. The reaction was quenched with IN aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was dried, concentrated and filtered through a bed of silica gel with 25% ethylacetate-hexanes. Trituration with methyltert-butylethrt/hexanes (1 :10) afforded the desired vinylketone 8g) as a white solid. 7g of this material were dissolved in 200mL of methanol and treated with 9g of cerium-lll-chloride heptahydrate, followed by 2g of sodium borohydride. The mixture was diluted with ethyl acetate and extracted with saturated aqueous amminium chloride. Drying and concentration in vacuo. followed by trituration with 10% ether.hexane afforded the desired alcohol as a 2:1 mixture of diastereomers (5g, white solid) which was dissolved in 50mL of 4M hydrogen chloride in 1,4-dioxane. The resulting solution was kept at 25° for lh and the volatiles were removed in vacuo. The residue was partitioned between ethylacetate and saturated aqueous sodium bicarbonate and the organic layer was dried and concentrated in vacuo to give the crude amino alcohol as a brown oil (2g). Step 2: A solution of biotinyl-p-bromophenylalanyl-1-naphthylalanine as obtained in Example 93 (l.Og, 1.8mMol) in 25mL of dimethylformamide was treated with 0.38g (2.2mMol) of the aminoalcohol obtained in Step 1, 0.41 g (2.2mMol) ofEDCI and 0.34g (2.2mMol) of N-hydroxybenzotriazoie. The resulting mixture was stirred at 25° for 12h and concentrated in vacuo. Trituration with ether afforded the desired alcohol as a white solid (1.lg). 0.7g (ImMol) of this compound were redissolved in lOOmL of chloroform and treated with 2.5g (15mMol) of m-chloroperbenzoic acid. The mixture was stirred at 25° for 15h and extracted with IN aqueous sodium hydroxide. Drying and concentration in vacuo afforded the desired epoxide as a white solid (0.8g). An aliquot (0.2g) of this compound was redissolved in 5mL of dimethylsulfoxide and treated with 1.5mL of acetic anhydride. The mixture was allowed to stand for 4 days and was then diluted with water. The precipitate was collected and washed with water. Chromatography on silica gel (5% me2hαncl/dichlorometh.ane) gave the desired ketoepoxide as a ca. 2:1 mixture oϊ diasteπsomers at the epoxide center. Further chromatography separated the diastereomers to produce two white solids (-0.01 g each). LRMS: diastereomer 1: 748/750 diastereomer 2: 748/750 Example 95 N-frbenzyloxy ^ )carbonv1]-L-isoleucvl-L-isoleucine-L-N-[l-rN-maleimidomethv1V2- d H-indol-3-yl thyl]amide Step 1. To a solution of 0.55g (lmmol) of the amine obtained in Step 3 of Example 82 in THF (25mL) was added 0.108g ( lmmol) of maleic anhydride. The resulting solution was stirred at room temperature overnight. Dilution with diethyl ether (75mL) followed by filtration of the resulting precipitate gave 0.17g of the desired amide as a yellow solid. The filtrate was further concentrated to give an additional 0.4g of the product. Step 2. To a solution of 50mg (0.08mmol) of the intermediate from Step 1, 5mg (0.04mmol) of DMAP and 0.3mL of pyridine in THF (5mL), pre-cooled at -30°C and under N , was added 0.2mL (l.όmmol) of cyanuric fluoride. The resulting solution was stirred at this temperature for lh and then allowed to warm to room temperature overnight. The mixture was partitioned between EtOAc and IN HCl. The organic layer was separated, washed with H2O, dried over MgSO4 and evaporated to dryness. The residue was chromatographed on preparative TLC plate eluted with CHCl3:MeOH/95:5. The desired band was extracted with THF. Evaporation of the solvent gave 2mg of the title compound as a solid. Step 1 : IH NMR (DMSO-d 6 ) 0.6-0.8 (12H), 1.1 (2H), 1.4 (2H), 1.7 (2H), 2.9 (2H), 3.1- 3.4 (4H), 3.95 (IH), 4.2 (2H), 5.0 (2H), 6.2 (IH), 6.3 (IH), 6.95 (IH), 7.0 (IH), 7.15 (IH), 7.3 (6H), 7.6 (IH), 7.8 (IH), 7.9 (IH), 10.8 (IH) LRMS: 665 (M+NH4) Anal: CHN Step 2: IH NMR (DMSO-d 6 ): 0.65-0.85 (12H), 1.1-1.6 (6H), 3.2-3.4 (4H), 3.5 (2H), 3.9 (2H), 4.1 (IH), 5.0 (2H). 6.85 (IH), 6.93 (2H), 7.0 (IH), 7.1 (IH), 7.3 (6H), 7.5 (IH), 7.65 (2H), 7.9 (IH), 8.0 (IH) LRMS: 630 (M+l) Example 96 N-ffbenzvloxv.carbonv -L-isoleucvl-L-isoleucine-L-N-p-π- methoxycarbonvloxa!vl]2-fphenvnethvl]amide Step 1: A mixture of 2.75g (5.2mmol) of CBZ-IIellePhe, assembled using the general procedures outlined above, 1.92g (5.7mmol) of methyltriphenylphosphoranylideneacetate (Aldrich), l.Og (5.2mmol) of EDCI and 60mg (0.5mmol) of 4-DMAP in CH2CI2 (200mL) was stirred to dissolve gradually at room temperature overnight. The resulting solution was washed with IN HCl and then saturated aqueous NaHCO3- The solution was dried over MgSO4 and evaporated to dryness. The residue was chromatographed on silica gel eluted with CHCI3 followed by CHCl3:EtOAc/9: 1 to give 1.7g of the desired phosphorane as a solid. Step 2: A mixture of 0.33g (0.4mmol) of the phosphorane obtained in Step 1 and l.Og (1.2mmol) of oxone in THF/H2O (10mL/8mL) was stirrred at room temperature overnight. The mixture was partitioned between EtOAc and H2O. The organic layer was separated, dried over M SO4 and evaporated to dryness. The residue was stirred in diethyl ether and sonicated. The insoluble white solid was filtered to give 0.038g of the title compound as a white solid. Step 1 : IH NMR (DMSO-d 6 ) 0.5-0.7 (12H), 1.0 (2H), 1.3 (2H), 1.6 (2H), 2.6 (IH), 2.96 (3H), 3.2 (IH), 3.85 (IH), 4.1 (IH), 5.0 (2H), 5.75 (IH), 7.1-7.2 (5H), 7.3 (5H), 7.5-7.6 (15H), 7.7 (IH), 7.8 (IH) LRMS: 842 (M+l) Anal: C,H,N,P Step 2: IH NMR (DMSO-d 6 ): 0.5-1.0 (12H), 1.05 (2H), 1.35 (2H), 1.6 (2H), 2.8-3.1 (2H), 3.53 (3H), 3.9 (IH), 4.2 (IH), 4.45 (IH), 5.0 (IH), 7.2 (5H), 7.3 (5H), 7.7 (IH), 8.4 (IH) LRMS: 596 (M+l) Example 97 N-Benzvloxvcarbonvl-S-cvclohexvlalanvl-S-fO-benzyl .tyrosyl-1 -S-formyl-l -(4- hromophenylmethylVmethylamide: IH NMR (δ, DMSO-d 6 ): 0.6-1.7 (11H), 2.6-3.2 (6H), 4.0-4.6 (3H), 5.0 (4H), 6.8-7.5 (19H), 8.0 (IH), 8.5 (IH), 9.3 (IH) LRMS: (Ion Spray): 768.3 (MH+) Example 98 N-Benzvloxvcarbonvl-S-rO-benzvntvrosvl-S-rO-benzvntvrosvl-l-S-fonrivl-1-C4- bromophenylmethyD-methylamide: IH NMR (δ, DMSO-d 6 ): 2.6-3.2 (6H), 4.2 (2H), 4.5 (IH), 5.0 (6H), 6.8-7.5 (28H), 8.2 (IH), 8.6 (IH), 9.3 (IH) LRMS: (Ion Spray): 868.2 (MH + ) Example 99 N-Benzyloxycarbonyl-S-rO-benzvntyrosyl-S-rO-ethvl.tvrosvl-1-S-formyl-1-f4- hromophenylmethylVmethylamide: IH NMR (δ, DMSO- 6 ): 2.6-3.2 (6H), 3.9 (2H), 4.2 (2H), 4.5 (IH), 5.0 (4H), 6.7-7.5 (23H), 8.2 (IH), 8.6 (IH), 9.3 (IH) LRMS: (Ion Spray): 806.4 (MH+) Example 100 N-Benzyloxycarbonyl-S-fO-ethyπtyrosyl-S- O-benzyl .tyrosyl-l -S-formyl-l -C4- bromophenylmethylVmethylamide: IH NMR (δ, DMSO-d 6 ): 1.4 (3H, 2.4-3.0 (6H), 4.0 (2H), 4.2 (IH), 5.0 (5H), 5.1 (IH), 6.7-7.6 (23H), 8.2 (IH), 8.6 (IH), 9.3 (IH) LRMS: (Ion Spray): 806.4 (MH + ) Example 101 IC values were determined as follows: 50 PORCINE AORTIC "ECE" PREP Porcine aortas (22-25) were obtained fresh from a local slaughterhouse and delivered in cold PBS on ice. The aortas were cut open, rinsed with cold PBS and the endothelial cell layer scraped into cold PBS using a scapel. The endothelial cells were pelleted by centrifugation, rinsed once with cold PBS, and repelleted. The pellet was lysed by addition of 10 volumes of lOmM Tris-HCl, pH 7.0, containing protease inhibitors and DTT, followed by brief sonication and homogenization. The lysate was centrifuged at 100,000g for 1 hour and the supernatant applied to a MONOQ FPLC anion exchange column equilibrated in lOmM Tris-HCl, . pΗ 7.0 (buffer A) which was then developed with an increasing gradient of NaCI in buffer A. The active fractions were aliquoted o and stored at -70 C. "ECE" ASSAY The ECE assay was performed in 96-well microplates in a total volume of 200μ/well. The assay cocktail contains lOOmM Tris-HCl, pH 7.0, 20mM CaCl , 80μM substrate (Suc-Ile-Ile-Trp-MCA), enzyme and test compounds. The test compounds were preincubated with the enzyme for 15-20 minutes before initiation of the assay by o addition of the substrate. The assay was incubated overnight at 37 C and the fluorescence intensity caused by the release of AMC was determined using a fluorescence microplate reader (EX360nm/EM460nm). IC values for compounds were determined by constructing concentration-effect curves for the inhibition of enzyme activity. Concentrations on the linear portion of the inhibition curve were used to determine the IC utilizing a Hill plot. Resulis Compounds I£ 511 dm ) Example 15 IC 50 (μM)=0.2 Example 16 IC 5 o(μM)=0.4 Example 17 IC 50 (μM) =4.4 Example 18 IC 50 (μM)=0.6 Example 19 Example 20 IC 50 (μM)=l.l Example 21 IC 50 (μM)=1.2 Example 22 IC 50 (μM)=4.0 Example 23 IC 50 (μM)=3.5 Example 24 IC 50 (μM)=1.5 Example 25 IC 50 (μM)=0.3 Example 26 IC 50 (μM)=1.5 Example 27 IC 50 (μM) =0.5 Example 28 IC 50 (μM)=0.2 Example 29 IC 50 (μM)=0.2 Example 30 IC 50 (μM)=0.2 Example 31 IC50 (μM) =0.06 Example 32 IC50 (μM) =0.1 Example 33 IC50 (μM) =0.2 Example 34 IC 50 (μM) =0.008 Example 35 IC50 (μM) =0.03 Example 36 IC50 (μM) =0.03 Example 37 IC50 (μM) =0.007 Example 38 1C 50 (μM) =0.008 Example 39 IC 50 (μM) =0.015 Example 40 IC50 (μM) =0.01 Example 41 IC50 (μM) =1.6 Example 42 IC50 (μM) =8 Example 43 IC50 (μM) =2 Example 44 IC50 (μM) =10 Example 45 IC 50 (μM) =0.2 Example 46 IC 50 (μM) =0.8 Example 47 IC50 (μM) =5 Example 48 IC50 (μM) =10 Example49 IC5ø(μM)=10 Example 50 IC50 (μM) =2 Example 51 IC5θ(μM)=10 Example 52 IC50 (μM) =2 Example 53 IC 5 o(μM)=10 Example 54 IC 50 (μM)=10 Example 55 IC50 (μM) =8 Example 56 IC50 (μM) =10 Example 57 IC50 (μM) =1 Example 58 IC5θ(μM)=0.1 Example 59 IC50 (μM) =0.1 Example 60 IC50 (μM) =1 Example 61 IC50 (μM) =0.8 Example 62 IC50 (μM) =2 Example 63 IC50 (μM) =0.03 Example 64 IC50 (μM) =0.06 Example 65 IC 50 (μM) =0.1 Example 66 IC50 (μM) =0.3 Example 67 IC50 (μM) =0.08 Example 68 IC50 (μM) =5 Example 69 IC50 (μM) =0.06 Example 70 IC50 (μM) =0.08 Example 71 IC50 (μM) =0.04 Example 72 IC 50 (μM) =0.15 Example 73 IC50 (μM) =8 Example 74 IC 50 (μM) =0.08 Example 75 IC50 (μM) =0.04 Example 76 IC50 (μM) =2.6 Example 77 IC50 (μM) =1 Example 78 IC50 (μM) =10 Example 79 IC50 (μM) =0.06 Example 80 IC5o (μM) =10 Example 81 IC 50 (μM) =0.2 Example 82 IC50 (μM) =10 Example 83 IC50 (μM) =1 Example 84 IC50 (μM) =1 Example 85 IC50 (μM =10 Example 86 IC50 (μM =10 Example 87 IC50 (μM =0.06 Example 88 IC50 (μM =0.6 Example 89 IC50 (μM =0.05 Example 90 IC50 (μM =0.06 Example 91 IC50 (μM =0.005 Example 92 IC50 (μM; =1 Example 93 IC50 (μM =0.002 Example 94 IC50 (μM; =0.006 Example 95 IC50 (μM =1 Example 96 IC50 (μM =10 Example 97 IC50 (μM; =10 Example 98 IC50 (μM = 1 Example 99 IC50 (μM =0.02 Example 100 IC50 (μM; =0.06

Claims: CLAIMS A compound of formula (I) or a salt thereof w ere n: R\ is C5.7 aryl; C5.7 aryl C\.η alkyl; C5.7 aryl C]_4 alkoxy; C5.7 aryloxy- Cj.4 alkyl; carboxy C]_4 alkyl; C]_4 alkoxycarbonyl Cj_4 alkyl; C]_4 alkyl or di-phenyl C1.4 alkyl, such aryl groups or aryl moieties of aryl-containing groups being optionally substituted with C1.4 alkyl, halo, nitro, carboxyl or sulphonyl, or Rj is a group of formula Ila, lib or He: where n = O or 1 : where n = O or 1 and where Z is -CONH- or -CH2- and R5 is benzyloxy; 1,2,3,6 tetrahydro-2,6-dioxo-4-pyrimidinyl; or 2,5 dioxo-4-imidazolidinyl; or where R is hydrogen or C 1 ^ 4 alkyl; R2 is indol-3-yl-methyl; C5.7 aryl; or C5.7 aryl Cj_4 alkyl, such aryl groups or aryl-moieties of aryl-containing groups being optionally substituted with hydroxy or halo; benzothienylmethyl; or C 1.4 alkyl; R3 is formyl; maleimidomethyl; methoxycarbonyl vinyl; dimethoxymethyl; semicarbazonomethyl; Cj_4 alkyl; R4 dithio; R4 dithio-Cj_4 alkyl; R4 dithioacetyl; R7 C1.4 aikylamido; R7 C]_4 alkylamidomethyl; - CORg; - CH(OH)Rα; -COCOR 10 ;or - COC s CRi 1, in which R4 is C1.4 alkyl, C5.7 aryl or C 1.4 alkyl C5.7 aryl; R7 is acetoxy, halo, maleimido or hydroxy; Rg is CH2 CH; CHO; C1.4 alkenyl, C1.4 alkylhalo or C 1.4 alkylthio; Ro is CHO, Cι_4 alkenyl or CH2-CH-, such oxiranyl moiety being optionally substituted with C]_4 alkyl or C 1.4 alkoxycarbonyl; R\Q is C1. alkoxy; C5.7 aryloxy; Cj_4 alkyl, hydrogen; hydroxy or methoxycarbonyl; and R\ j is hydrogen or Si(CH3); such aryl groups or aryl moieties of aryl-containing groups being optionally substituted widi nitro or carboxy; X is benzyl optionally substituted with C]_4 alkoxy or halo; Cι_4 alkyl; indol-3- yl-methyl; naphthylmethyl; benzyloxybenzyl or cyclo C\. alkylmethyl; and Y is benzyl optionally substituted with C}_4 alkyl or C 1.4 alkoxy; indol-3-yl- methyl; naphthylmethyl; benzyloxybenzyl or Cj_4 alkyl. 2. A compound according to Claim 1, wherein R\ is C5.7 aryl Cι_4 alkoxy; C5.7 aryl C]_4 alkyl; C5.7 aryloxy C1.4 alkyl or is a group of Formula Ila or lib where n=O or 1 and where Z is -CONH-or-CH2 and R5 is benzyloxy; 1,2,3,6 tetr.ahydro-2,6-dioxo-4-pyrimidinyl or 2,5,dioxo-4-imidazolidinyl, or is a group of Formula lie where R is hydrogen or C 1.4 alkyl. 3. A compound according to Claim 1, wherein R2 indol-3yl-methyl; phenyl or benzyl optionally substituted with halo or hydroxy. 4. A compound according to claim 1, wherein R3 is formyl; semicarbazonomethyl; -CORg; R7 C ] _4 aikylamido or R7 Cj^. alkylamidomethyl; in which Rg is CH2 CH-; CHO; C j ^ alkenyl, Cj. alkylhalo or Cj^ alkylthio and R7 is acetoxy, halo, maleimido, or hydroxy. 5. A compound according to claim 1 , wherein X is benzyl optionally substituted with halo; indol- 3-yl-methyl; naphthylmethyl; Cι_4 alkyl; or benzyloxybenzyl. 6. A compound according to claim 1, wherein Y is naphthylmethyl; indol-3-yl- methyl; benzyloxybenzyl; Cj^ alkyl; benzyloxyCj_4 alkyl. 7. A compound according to claim 2, wherein Rj is benzyloxy; [5-(hexahydro-2- oxo-lH-thieno(3,4-d] imidazol-4-yl) valeramido]pentyl; 6-[6-[(l, 2,3,6- tetrahydro-2,6-dioxo-4-pyrimidinyl) formamido] hexanamido] pentyl; 6-[6- (benzyloxy) formamido] hexanamido] pentyl; 12-[(benzyloxy) acetamido] undecanyl; 5-phenylbutyl; phenoxyethyl; 5-(hexahydro-2-oxo-(lH-thieno(3,4-d) imidazol-4-yl)butyl; 3-pyridylmethoxy; benzyl; 2-phenylethyl, 3-phenylethyl; N-[(benzyloxy) carbonyl)]-4-O-tert-butyl-L-aspart-l-yl; N- [(benzyloxy) carbonyl)] -L-aspart- 1 -yl; 6-[6-[2-(2,5-dioxo-4-imidazolidinyl) acetamido] hexanamido] pentyl; 3-pyridylmethoxy; 6-benzyloxycarbonyl- aminopentyl. 8. A compound according to claim 3, wherein R2 is indol-3-yl methyl, chlorobenzyl; bromobenzyl; phenyl; benzyl, 4-hydroxybenzyl. 9. A compound according to claim 4, wherein R3 is formyl; 2-oxiranylcarbonyl; semicarbazonomethyl; glyoxyloyl; acryloyl; chloroacetyl; 2-chIoroacetyl; 2- acetoxyacetamido; (2-chloro-acetamido) methyl; (2-maleimidoacetamido)- methyl; 3-(malemidoacetamido)-methyl; 1-maleimidomethyl; propynoyl; (3- maleimidopropionamido) methyl. 10. A compound according to claim 5, wherein X is indol-3-yl-methyl; bromobenzyl; 1-napthylmethyl; iodobenzyl; benzyloxybenzyl; [S]-l- methylpropyl; 2-napthylmethyl; benzyl; methyl; 4-chlorobenzyl; 2-methyl- propyl; 1-methylethyl. 11. A compound according to claim 6, wherein Y is indol-3-yl-methyl; 1'- naphthylmethyl; 2-napthylmethyl; benzyloxybenzyl; 4-ethoxybenzyl; [S]- methylpropyl and, 1-methylethyl. 12. A compound according to claim 7, wherein Rj is benzyloxy or 5-(hexahydro-2- oxo-lH-thieno [3,4-d] imidazol-4-yl) butyl. 13. A compound according to claim 8, wherein R2 is indol-3-yl-methyl, or phenyl. 14. A compound according to claim 9, wherein R3 is formyl, semicarbazonomethyl or 2-oxiranylcarbonyl. 15. A compound according to claim 10, wherein X is indol-3-yl-methyl, bromobenzyl or [S]-l-methylpropyl. 16. A compound according to claim 1 1 , "wherein Y is indol-3-yl-methyl, l'naphthylmethyl, 2-naphthylmethj.1 or Sj-l-methylpropyl. 17. A compound according to any preceding claim, wherein Rj is 5-(hexahydro-2- oxo-lH thieno [3,4-d] imidazol-4-yl) butyl or benzyloxy; R2 is indol-3-yl- methyl or phenyl and R3 is formyl or oxiranylcarbonyl. 18. A compound according to any preceding claim, wherein X is bromobenzyl, iodobenzyl or indol-3-yl-methyl, and Y is 2-napthylmethyl or indol-3-yl-methyl. 19. N-[5-(hexahydro-2-oxo-lH-thieno[3,4-d]imidazol-4-yl)pentanoyl]-l-p- bromophenylalany 1-L- 1 -naphthylalany 1-L-N- [ 1 -formy l]2-( 1 H-indol-3- yl)ethyl]amide; or N- [5 -(hexahydro-2-oxo- 1 H-thieno [3,4-d] imidazol-4-y l)pentanoy 1]-L- tryptophanyl-L-tryptophan-L-N-[l-formyl]2-(lH-indol-3-yl)ethyl]amide; or N-(benzyloxy)carbonyl-L-p-bromophenylalanyl-L- 1 -naphthylalanyl-L-N-[ 1 - {2- oxiranylcarbonyl]]2-phenylethyl]amide; or N-Benzyloxycarbonyl-S-p-bromophenylalanyl-S- 1 'naphthylalanyl- 1 -S-formyl- 1 ■ (lH-indol-3-yl-methyl)-methylamide; or N-Benzyloxycarbonyl-S-p-bromophenylalanyl-S-2'naphthyl.alanyl- 1 -S-formyl- 1 - ( 1 H-indol-3 -y l-methyl)-methylamide ; or N-Benzyloxycarbonyl-S-tryptophanyl-S- 1 'naphthylalanyl- 1 -S-formyl- 1 -( 1 H- indol-3-yl-methyl)-methylamide; N-Benzyloxycarbonyl-S-p-iodophenylalanyl-S- 1 'naphthylalanyl- 1 -S-formyl- 1 - (lH-indol-3-yl-methyl)-methylamide; or a salt thereof. 20. N-[5-(hexahydro-2-oxo-lH-thieno[3,4-d]imidazol-4-yl)pentanoyl]-L-p- bromophenylalanyl-L- 1 -naphthylalanyl-L-N-[l -formyl]2-( 1 H-indol-3- yl)ethyl]amide; or N-[5-(hexahydro-2-oxo-lH-thieno[3,4-d]imidazol-4-yl)pentanoyl]-L- tryptophanyl-L-tryptophan-L-N-[l-formyl]2-(lH-indol-3-yl)ethyl]amide;or N-(benzyloxy)carbonyl-L-p-bromophenylalanyl-L- 1 -naphthylalanyl-L-N-[ 1 -[2- oxiranylcarbonyl]]2-phenylethyl]amide; or N-Benzyloxycarbonyl-S-p-bromophenylalanyl-S-1 'naphthylalanyl- 1 -S-formyl- 1 - (lH-indol-3-yl-methyl)-methylamide; or a salt thereof. 21. N-Benzyloxycarbonyl-S-p-bromophenylalanyl-S- 1 'naphthylalanyl- 1 -S-formyl- 1 - (lH-indol-3-yl-methyl)-methylamide; or a salt thereof. 22. A compound of formula III or a salt thereof III R\ is selected from the group comprising C5.7 aryl; C5.7 aryl C1.4 alkyl; carboxy C ^ alkyl; C1.4 alkyl and C5.7 aryl Cj_4 alkoxy; such aryl groups or aryl moieties of aryl-containing groups being optionally substituted with Cj_4 alkyl, halo, nitro, carboxyl or sulphonyl; wherein R2' is methyl R2 and R2> is selected from the group comprising indol-3-yl; phenyl; isobutyl and benzothienyl; and R3 is selected from the group comprising formyl; glyoxyloyl; haloacetyl; Cι_4 alkoxalyl; C5.7 aryloxalyl;R4 dithio;R4 dithio C j _ alkyl;R4 dithioacetyl; \^ alkyl ;acryloyl and 2-oxiranylcarbonyl such oxiranyl being optionally substituted with a Cι_4 alkyl or Cι_4 alkoxycarbonyl and R4 is selected from the group comprising Cι_4 alkyl, C5.7 aryl and C1.4 alkyl C5.7 aryl; such aryl groups or aryl moieties of aryl-containing groups being optionally substituted with nitro or carboxyl. 23. N-Benzyloxycarbonyl-L-isoleucyl-L-isoleucine-L-N-[l-[2-oxiranylcarbonyl]-2- (phenyl)ethyl]amide; or a salt thereof. 24. A pharmaceutical composition comprising a compound or salt thereof according to any of the preceding claims and a pharmaceutically acceptable carrier. 25. A compound or salt thereof according to any of Claims 1 to 23 for use in a method of inhibiting endothelin converting enzyme. 26. A compound or salt thereof according to any of Claims 1 to 23 for use in a method of treatment of cardiovascular disease. 27. A compound or salt thereof according to Claim 26 for use in a method of treatment of myocardial infarction, angina pectoris, cerebral infarction (stroke), cerebral vasospasm, ischemic cardiac insufficiency, Raynaud's disease and other vasospastic diseases, atherosclerosis, essential hypertension, pulmonary hypertension, asthma, respiratory distress syndrome, acute renal failure, cyclosporin-induced renal failure, endotoxic shock, endotoxin-induced multiple organ failure and actue failure following organ transplantation. 28. A compound or salt thereof according to any of Claims 1 to 23 for treatment of Crohn's disease, ulcerative colitis and gastric ulcers. 29. A compound or salt thereof according to any of Claims 1 to 23 for treatment of escleroderma and lupus erythematosus.

Inventors: LEBAN JOHANN JAKOB, SHERMAN DOUGLAS BYRON, SIGAFOOS JAMES FREDERICK, SPALTENSTEIN ANDREAS, VIVEROS OSVALDO HUMBERTO, WAN DAVID CHI-CHEONG, LEBAN, JOHANN, JAKOB, SHERMAN, DOUGLAS, BYRON, SIGAFOOS, JAMES, FREDERICK, SPALTENSTEIN, ANDREAS, VIVEROS, OSVALDO, HUMBERTO, WAN, DAVID, CHI-CHEONG
Applicants: LEBAN JOHANN JAKOB, SHERMAN DOUGLAS BYRON, SIGAFOOS JAMES FREDERICK, SPALTENSTEIN ANDREAS, VIVEROS OSVALDO HUMBERTO, WAN DAVID CHI CHEONG, WELLCOME FOUND, LEBAN, JOHANN, JAKOB, SHERMAN, DOUGLAS, BYRON, SIGAFOOS, JAMES, FREDERICK, SPALTENSTEIN, ANDREAS, THE WELLCOME FOUNDATION LIMITED, VIVEROS, OSVALDO, HUMBERTO, WAN, DAVID, CHI-CHEONG
Application year: 1994
Main classification: C07K5
IPC codes: A61K38, A61P1, A61P9, A61P11, A61P13, A61P15, C07K5, C07K7